3,5-diaminopyrazole kinase inhibitors

ABSTRACT

Provided herein are 3,5-diaminopyrazoles, for example, compounds of Formula I, that are useful for modulating regulated-in-COPD kinase activity, and pharmaceutical compositions thereof. Also provided herein are methods of their use for treating, preventing, or ameliorating one or more symptoms of a RC kinase-mediated disorder, disease, or condition.

This application claims the benefit of priority to U.S. ProvisionalPatent Application Ser. No. 62/096,308, filed Dec. 23, 2014, thedisclosure of which is incorporated by reference herein in its entirety.

FIELD

Provided herein are 3,5-diaminopyrazoles that are useful for modulatingregulated-in-COPD kinase (RC kinase) activity, and pharmaceuticalcompositions thereof. Also provided herein are methods of their use fortreating, preventing, or ameliorating one or more symptoms of a RCkinase-mediated disorder, disease, or condition.

BACKGROUND

Regulated-in-COPD kinase (RC kinase) is closely related to MAPKKK3,which directly regulates the pathways of stress-activated protein kinase(SAPK) and extracellular signal-regulated protein kinase (ERK) byactivating SEK and MEK1/2, respectively. See, U.S. Pat. No. 7,829,685,the disclosure of which is incorporated herein by reference in itsentirety. RC kinase is an upstream activator in MAP kinase signalingcascades, capable of phosphorylating MAP kinase kinases such as MKK4 andMKK6. The activation of MKK4 leads to the phosphorylation of JNK-typeMAP kinases, leading to the phosphorylation of c-Jun and thus theactivation of the AP-1 transcription factor complex. As a result,interleukin-8 production is increased, leading to the recruitment ofinflammatory cells, such as neutrophils. The activation of MKK6 leads tothe phosphorylation of p38-type MAP kinases, which is important in theactivation of the immune response and key regulators of inflammatorycytokine expression. The occurrence of cellular stresses, the activationof the transcription factor, and the overproduction of interleukin-8 arecharacteristic of numerous inflammatory diseases. Thus, the regulationof RC kinase activity can potentially be beneficial to patients withinflammatory diseases.

RC kinase has been shown to be highly expressed in the lung and trachea.Some of the expressed sequence tags of human RC kinase are alsoexpressed in the lung epithelial cells and in primary lung cysticfibrosis epithelial cells. Microarray analyses of patients with chronicobstructive pulmonary disease (COPD) show that RC kinase is upregulatedin the lungs of COPD patients. On the cellular level, it has been shownthat the expression of RC kinase is upregulated in response tohyperosmotic or oxidative stress. For example, the expression of RCkinase in cells increases significantly after exposure to potassiumchloride or hydrogen peroxide. Potassium chloride subjects cells to ahyperosmotic stress. Hydrogen peroxide subjects cells to an oxidativestress, which impairs the capacity of B cells to stimulate specific Tcells. Such upregulation of RC kinase in cells in response tohyperosmotic and oxidative stress suggests that higher expression of RCkinase in lungs of COPD patients may be the result of cellular stressescaused by the irritants in tobacco smoke or stresses caused byinflammatory response to those irritants.

Therefore, RC kinase inhibitors are potentially useful for the treatmentof inflammatory diseases, including COPD.

Janus Kinase (JAK) is a family of intracellular, nonreceptor tyrosinekinases that transduce cytokine-mediated signals via the JAK/STATsignaling pathway. This family, comprising JAK1, JAK2, JAK3 and TYK2(tyrosine kinase 2), was first described more than 20 years ago, but thecomplexities underlying their activation, regulation and pleiotropicsignaling functions are still being explored. See, e.g., Babon et al.,Biochem 1 2014; 462(1), 1-13. Disrupted or dysregulated JAK-STATfunctionality may result in a variety of disorders, including immunedeficiency syndromes and cancers. Aaronson et al., Science 2002, 296,1653-1655. The primary challenge with most kinase inhibitor programsaimed at non-oncologic indications is to define the degree ofselectivity required across the kinome that will limit the off-targetkinase induced side effect profile of a potential drug. Designing incompound selectivity across the kinome is difficult due to the highlyconserved structure within the kinase active site. See, e.g., Rokosz etal., Expert Opin. Ther. Targets 2008, 12(7) 883-903; Bhattacharya etal., Biochemical and Biophysical Research Communications 2003, 307,267-273.

Since disrupting the JAK-STAT pathway may lead to unwanted side effects,development of a therapeutic that can inhibit RC kinase expression whileminimally affecting the function of JAK is of great importance.

SUMMARY OF THE DISCLOSURE

Provided herein is a 3,5-diaminopyrazole of Formula I:

or a stereoisomer, enantiomer, mixture of enantiomers, mixture ofdiastereomers, or isotopic variant thereof; or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof; wherein:

R¹ is C₆₋₁₄ aryl, heteroaryl, or heterocyclyl;

R² and R³ are each independently C₁₋₆ alkyl or C₃₋₁₀ cycloalkyl;

wherein each alkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl isoptionally substituted with one or more substituents Q, where each Q isindependently selected from halo, C₁₋₆ alkyl, heteroaryl, andheterocyclyl, each of which is further optionally substituted with oneor more C₁₋₆ alkyl;

with the proviso that the compound is not3-((3-chlorophenyl)amino)-5-((4-hydroxy-3,5-dimethylbenzyl)amino)-1H-pyrazole-4-carboxamide.

In another embodiment, provided herein is a 3,5-diaminopyrazole ofFormula I:

or a stereoisomer, enantiomer, mixture of enantiomers, mixture ofdiastereomers, or isotopic variant thereof; or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof; wherein:

R¹ is C₆₋₁₄ aryl, heteroaryl, or heterocyclyl;

R² and R³ are each independently C₁₋₆ alkyl or C₃₋₁₀ cycloalkyl;

wherein each alkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl isoptionally substituted with one or more substituents Q, where each Q isindependently selected from halo, amino, aminosulfonyl, C₁₋₆ alkyl, C₁₋₆alkoxy, alkylamido, cyano, aryl, heteroaryl, and heterocyclyl, each ofwhich is further optionally substituted with one or more C₁₋₆ alkyl,halo, cyano, oxo, aralkyl, dialkylamino, arylamido, heterocyclyl,heterocyclylalkyl, and heterocyclylcarbonyl;

with the proviso that the compound is not3-((3-chlorophenyl)amino)-5-((4-hydroxy-3,5-dimethylbenzyl)amino)-1H-pyrazole-4-carboxamide.

Also provided herein are pharmaceutical compositions comprising acompound disclosed herein, e.g., a compound of Formula I, including astereoisomer, enantiomer, mixture of enantiomers, mixture ofdiastereomers, or isotopic variant thereof; or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof; and one or morepharmaceutically acceptable excipients.

Further provided herein is a method of treating, preventing, orameliorating one or more symptoms of a RC kinase-mediated disorder,disease, or condition in a subject, comprising administering to thesubject a therapeutically effective amount of a compound disclosedherein, e.g., a compound of Formula I, including a stereoisomer,enantiomer, mixture of enantiomers, mixture of diastereomers, orisotopic variant thereof; or a pharmaceutically acceptable salt,solvate, hydrate, or prodrug thereof.

Additionally provided herein is a method of modulating RC kinaseactivity, comprising contacting a RC kinase with a therapeuticallyeffective amount of a compound disclosed herein, e.g., a compound ofFormula I, including a stereoisomer, enantiomer, mixture of enantiomers,mixture of diastereomers, or isotopic variant thereof; or apharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

Also provided herein is a method of treating, preventing, orameliorating one or more symptoms of a RC kinase-mediated disorder,disease, or condition in a subject, comprising administering to thesubject a therapeutically effective amount of a compound disclosedherein, e.g., a compound of Formula I, including a stereoisomer,enantiomer, mixture of enantiomers, mixture of diastereomers, orisotopic variant thereof; or a pharmaceutically acceptable salt,solvate, hydrate, or prodrug thereof, wherein the compound displaysincreased potency against RC kinase and/or increased RC kinase to JAK2selectivity and/or increased RC kinase to JAK3 selectivity.

DETAILED DESCRIPTION

To facilitate understanding of the disclosure set forth herein, a numberof terms are defined below.

Generally, the nomenclature used herein and the laboratory procedures inorganic chemistry, medicinal chemistry, and pharmacology describedherein are those well known and commonly employed in the art. Unlessdefined otherwise, all technical and scientific terms used hereingenerally have the same meaning as commonly understood by one ofordinary skill in the art to which this disclosure belongs.

The term “subject” refers to an animal, including, but not limited to, aprimate (e.g., human), cow, pig, sheep, goat, horse, dog, cat, rabbit,rat, or mouse. The terms “subject” and “patient” are usedinterchangeably herein in reference, for example, to a mammaliansubject, such as a human subject, in one embodiment, a human.

The terms “treat,” “treating,” and “treatment” are meant to includealleviating or abrogating a disorder, disease, or condition, or one ormore of the symptoms associated with the disorder, disease, orcondition; or alleviating or eradicating the cause(s) of the disorder,disease, or condition itself.

The terms “prevent,” “preventing,” and “prevention” are meant to includea method of delaying and/or precluding the onset of a disorder, disease,or condition, and/or its attendant symptoms; barring a subject fromacquiring a disorder, disease, or condition; or reducing a subject'srisk of acquiring a disorder, disease, or condition.

The term “therapeutically effective amount” are meant to include theamount of a compound that, when administered, is sufficient to preventdevelopment of, or alleviate to some extent, one or more of the symptomsof the disorder, disease, or condition being treated. The term“therapeutically effective amount” also refers to the amount of acompound that is sufficient to elicit the biological or medical responseof a biological molecule (e.g., a protein, enzyme, RNA, or DNA), cell,tissue, system, animal, or human, which is being sought by a researcher,veterinarian, medical doctor, or clinician.

The term “IC₅₀” or “EC₅₀” refers an amount, concentration, or dosage ofa compound that is required for 50% inhibition of a maximal response inan assay that measures such response.

The term “CC₅₀” refers an amount, concentration, or dosage of a compoundthat results in 50% reduction of the viability of a host. In certainembodiments, the CC₅₀ of a compound is the amount, concentration, ordosage of the compound that is required to reduce the viability of cellstreated with the compound by 50%, in comparison with cells untreatedwith the compound.

The term “pharmaceutically acceptable carrier,” “pharmaceuticallyacceptable excipient,” “physiologically acceptable carrier,” or“physiologically acceptable excipient” refers to apharmaceutically-acceptable material, composition, or vehicle, such as aliquid or solid filler, diluent, solvent, or encapsulating material. Inone embodiment, each component is “pharmaceutically acceptable” in thesense of being compatible with the other ingredients of a pharmaceuticalformulation, and suitable for use in contact with the tissue or organ ofhumans and animals without excessive toxicity, irritation, allergicresponse, immunogenicity, or other problems or complications,commensurate with a reasonable benefit/risk ratio. See, Remington: TheScience and Practice of Pharmacy, 21st ed.; Lippincott Williams &Wilkins: Philadelphia, Pa., 2005; Handbook of Pharmaceutical Excipients,6th ed.; Rowe et al., Eds.; The Pharmaceutical Press and the AmericanPharmaceutical Association: 2009; Handbook of Pharmaceutical Additives,3rd ed.; Ash and Ash Eds.; Gower Publishing Company: 2007;Pharmaceutical Preformulation and Formulation, 2nd ed.; Gibson Ed.; CRCPress LLC: Boca Raton, Fla., 2009.

The term “about” or “approximately” means an acceptable error for aparticular value as determined by one of ordinary skill in the art,which depends in part on how the value is measured or determined. Incertain embodiments, the term “about” or “approximately” means within 1,2, 3, or 4 standard deviations. In certain embodiments, the term “about”or “approximately” means within 50%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%,4%, 3%, 2%, 1%, 0.5%, or 0.05% of a given value or range.

The terms “active ingredient” and “active substance” refer to acompound, which is administered, alone or in combination with one ormore pharmaceutically acceptable excipients, to a subject for treating,preventing, or ameliorating one or more symptoms of a disorder, disease,or condition. As used herein, “active ingredient” and “active substance”may be an optically active isomer or an isotopic variant of a compounddescribed herein.

The terms “drug,” “therapeutic agent,” and “chemotherapeutic agent”refer to a compound, or a pharmaceutical composition thereof, which isadministered to a subject for treating, preventing, or ameliorating oneor more symptoms of a disorder, disease, or condition.

The term “alkyl” refers to a linear or branched saturated monovalenthydrocarbon radical, wherein the alkyl is optionally substituted withone or more substituents Q as described herein. For example, C₁₋₆ alkylrefers to a linear saturated monovalent hydrocarbon radical of 1 to 6carbon atoms or a branched saturated monovalent hydrocarbon radical of 3to 6 carbon atoms. In certain embodiments, the alkyl is a linearsaturated monovalent hydrocarbon radical that has 1 to 20 (C₁₋₂₀), 1 to15 (C₁₋₁₅), 1 to 10 (C₁₋₁₀), or 1 to 6 (C₁₋₆) carbon atoms, or branchedsaturated monovalent hydrocarbon radical of 3 to 20 (C₃₋₂₀), 3 to 15(C₃₋₁₅), 3 to 10 (C₃₋₁₀), or 3 to 6 (C₃₋₆) carbon atoms. As used herein,linear C₁₋₆ and branched C₃₋₆ alkyl groups are also referred as “loweralkyl.” Examples of alkyl groups include, but are not limited to,methyl, ethyl, propyl (including all isomeric forms), n-propyl,isopropyl, butyl (including all isomeric forms), n-butyl, isobutyl,sec-butyl, t-butyl, pentyl (including all isomeric forms), and hexyl(including all isomeric forms).

The term “alkenyl” refers to a linear or branched monovalent hydrocarbonradical, which contains one or more, in one embodiment, one to five, inanother embodiment, one, carbon-carbon double bond(s), wherein thealkenyl is optionally substituted with one or more substituents Q asdescribed herein. The term “alkenyl” embraces radicals having a “cis” or“trans” configuration or a mixture thereof, or alternatively, a “Z” or“E” configuration or a mixture thereof, as appreciated by those ofordinary skill in the art. For example, C₂₋₆ alkenyl refers to a linearunsaturated monovalent hydrocarbon radical of 2 to 6 carbon atoms or abranched unsaturated monovalent hydrocarbon radical of 3 to 6 carbonatoms. In certain embodiments, the alkenyl is a linear monovalenthydrocarbon radical of 2 to 20 (C₂₋₂₀), 2 to 15 (C₂₋₁₅), 2 to 10(C₂₋₁₀), or 2 to 6 (C₂₋₆) carbon atoms, or a branched monovalenthydrocarbon radical of 3 to 20 (C₃₋₂₀), 3 to 15 (C₃₋₁₅), 3 to 10(C₃₋₁₀), or 3 to 6 (C₃₋₆) carbon atoms. Examples of alkenyl groupsinclude, but are not limited to, ethenyl, propen-1-yl, propen-2-yl,allyl, butenyl, and 4-methylbutenyl.

The term “alkynyl” refers to a linear or branched monovalent hydrocarbonradical, which contains one or more, in one embodiment, one to five, inanother embodiment, one, carbon-carbon triple bond(s), wherein thealkynyl is optionally substituted with one or more substituents Q asdescribed herein. For example, C₂₋₆ alkynyl refers to a linearunsaturated monovalent hydrocarbon radical of 2 to 6 carbon atoms or abranched unsaturated monovalent hydrocarbon radical of 3 to 6 carbonatoms. In certain embodiments, the alkynyl is a linear monovalenthydrocarbon radical of 2 to 20 (C₂₋₂₀), 2 to 15 (C₂₋₁₅), 2 to 10(C₂₋₁₀), or 2 to 6 (C₂₋₆) carbon atoms, or a branched monovalenthydrocarbon radical of 3 to 20 (C₃₋₂₀), 3 to 15 (C₃₋₁₅), 3 to 10(C₃₋₁₀), or 3 to 6 (C₃₋₆) carbon atoms. Examples of alkynyl groupsinclude, but are not limited to, ethynyl (—C≡CH), propynyl (includingall isomeric forms, e.g., 1-propynyl (—C≡CCH₃) and propargyl(—CH₂C≡CH)), butynyl (including all isomeric forms, e.g., 1-butyn-1-yland 2-butyn-1-yl), pentynyl (including all isomeric forms, e.g.,1-pentyn-1-yl and 1-methyl-2-butyn-1-yl), and hexynyl (including allisomeric forms, e.g., 1-hexyn-1-yl).

The term “cycloalkyl” refers to a cyclic monovalent hydrocarbon radical,wherein the cycloalkyl is optionally substituted with one or moresubstituents Q as described herein. In one embodiment, cycloalkyl groupsmay be saturated or unsaturated but non-aromatic, and/or spiro, and/ornon-spiro, and/or bridged, and/or non-bridged, and/or fused bicyclicgroups. In certain embodiments, the cycloalkyl has from 3 to 20 (C₃₋₂₀),from 3 to 15 (C₃₋₁₅), from 3 to 10 (C₃₋₁₀), or from 3 to 7 (C₃₋₇) carbonatoms. Examples of cycloalkyl groups include, but are not limited to,cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl,cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptenyl,bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, decalinyl, and adamantyl.

The term “aryl” refers to a monovalent monocyclic aromatic group and/ormonovalent polycyclic aromatic group that contain at least one aromaticcarbon ring, wherein the aryl is optionally substituted with one or moresubstituents Q as described herein. In certain embodiments, the aryl hasfrom 6 to 20 (C₆₋₂₀), from 6 to 15 (C₆₋₁₅), or from 6 to 10 (C₆₋₁₀) ringatoms. Examples of aryl groups include, but are not limited to, phenyl,naphthyl, fluorenyl, azulenyl, anthryl, phenanthryl, pyrenyl, biphenyl,and terphenyl. Aryl also refers to bicyclic or tricyclic carbon rings,where one of the rings is aromatic and the others of which may besaturated, partially unsaturated, or aromatic, for example,dihydronaphthyl, indenyl, indanyl, or tetrahydronaphthyl (tetralinyl).

The term “aralkyl” or “arylalkyl” refers to a monovalent alkyl groupsubstituted with one or more aryl groups, wherein the aralkyl orarylalkyl is optionally substituted with one or more substituents Q asdescribed herein. In certain embodiments, the aralkyl has from 7 to 30(C₇₋₃₀), from 7 to 20 (C₇₋₂₀), or from 7 to 16 (C₇₋₁₆) carbon atoms.Examples of aralkyl groups include, but are not limited to, benzyl,2-phenylethyl, and 3-phenylpropyl.

The term “heteroaryl” refers to a monovalent monocyclic aromatic groupor monovalent polycyclic aromatic group that contain at least onearomatic ring, wherein at least one aromatic ring contains one or moreheteroatoms independently selected from O, S, N, and P in the ring.Heteroaryl groups are bonded to the rest of a molecule through thearomatic ring. Each ring of a heteroaryl group can contain one or two Oatoms, one or two S atoms, one to four N atoms, and/or one or two Patoms, provided that the total number of heteroatoms in each ring isfour or less and each ring contains at least one carbon atom. In certainembodiments, the heteroaryl has from 5 to 20, from 5 to 15, or from 5 to10 ring atoms. Examples of monocyclic heteroaryl groups include, but arenot limited to, furanyl, imidazolyl, isothiazolyl, isoxazolyl,oxadiazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl,pyridyl, pyrimidinyl, pyrrolyl, thiadiazolyl, thiazolyl, thienyl,tetrazolyl, triazinyl, and triazolyl. Examples of bicyclic heteroarylgroups include, but are not limited to, benzofuranyl, benzimidazolyl,benzoisoxazolyl, benzopyranyl, benzothiadiazolyl, benzothiazolyl,benzothienyl, benzotriazolyl, benzoxazolyl, furopyridyl,imidazopyridinyl, imidazothiazolyl, indolizinyl, indolyl, indazolyl,isobenzofuranyl, isobenzothienyl, isoindolyl, isoquinolinyl,isothiazolyl, naphthyridinyl, oxazolopyridinyl, phthalazinyl,pteridinyl, purinyl, pyridopyridyl, pyrrolopyridyl, quinolinyl,quinoxalinyl, quinazolinyl, thiadiazolopyrimidyl, and thienopyridyl.Examples of tricyclic heteroaryl groups include, but are not limited to,acridinyl, benzindolyl, carbazolyl, dibenzofuranyl, perimidinyl,phenanthrolinyl, phenanthridinyl, phenarsazinyl, phenazinyl,phenothiazinyl, phenoxazinyl, and xanthenyl. In certain embodiments, theheteroaryl is optionally substituted with one or more substituents Q asdescribed herein.

The term “heteroaralkyl” or “heteroarylalkyl” refers to a monovalentalkyl group substituted with one or more heteroaryl groups, wherein thealkyl and heteroaryl are each as defined herein. In certain embodiments,the heteroaralkyl is optionally substituted with one or moresubstituents Q as described herein.

The term “heterocyclyl” or “heterocyclic” refers to a monovalentmonocyclic non-aromatic ring system or monovalent polycyclic ring systemthat contains at least one non-aromatic ring, wherein one or more of thenon-aromatic ring atoms are heteroatoms independently selected from O,S, N, and P; and the remaining ring atoms are carbon atoms. In certainembodiments, the heterocyclyl or heterocyclic group has from 3 to 20,from 3 to 15, from 3 to 10, from 3 to 8, from 4 to 7, or from 5 to 6ring atoms. Heterocyclyl groups are bonded to the rest of a moleculethrough the non-aromatic ring. In certain embodiments, the heterocyclylis a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, whichmay be spiro, fused, or bridged, and in which nitrogen or sulfur atomsmay be optionally oxidized, nitrogen atoms may be optionallyquaternized, and some rings may be partially or fully saturated, oraromatic. The heterocyclyl may be attached to the main structure at anyheteroatom or carbon atom which results in the creation of a stablecompound. Examples of such heterocyclic groups include, but are notlimited to, azepinyl, benzodioxanyl, benzodioxolyl, benzofuranonyl,benzopyranonyl, benzopyranyl, benzotetrahydrofuranyl,benzotetrahydrothienyl, benzothiopyranyl, benzoxazinyl, β-carbolinyl,chromanyl, chromonyl, cinnolinyl, coumarinyl, decahydroisoquinolinyl,dihydrobenzisothiazinyl, dihydrobenzisoxazinyl, dihydrofuryl,dihydroisoindolyl, dihydropyranyl, dihydropyrazolyl, dihydropyrazinyl,dihydropyridinyl, dihydropyrimidinyl, dihydropyrrolyl, dioxolanyl,1,4-dithianyl, furanonyl, imidazolidinyl, imidazolinyl, indolinyl,isobenzotetrahydrofuranyl, isobenzotetrahydrothienyl, isochromanyl,isocoumarinyl, isoindolinyl, isothiazolidinyl, isoxazolidinyl,morpholinyl, octahydroindolyl, octahydroisoindolyl, oxazolidinonyl,oxazolidinyl, oxiranyl, piperazinyl, piperidinyl, 4-piperidonyl,pyrazolidinyl, pyrazolinyl, pyrrolidinyl, pyrrolinyl, quinuclidinyl,tetrahydrofuryl, tetrahydroisoquinolinyl, tetrahydropyranyl,tetrahydrothienyl, thiamorpholinyl, thiazolidinyl, tetrahydroquinolinyl,and 1,3,5-trithianyl. In certain embodiments, the heterocyclyl isoptionally substituted with one or more substituents Q as describedherein.

The term “heterocyclylalkyl” refers to a monovalent alkyl groupsubstituted with one or more heterocyclyl groups, wherein the alkyl andheterocyclyl are each as defined herein. In certain embodiments, theheteroaralkyl is optionally substituted with one or more substituents Qas described herein.

The term “alkoxy” refers to —O-alkyl, wherein the alkyl is as definedherein. For example, the term “C₁₋₆ alkoxy” refers to —O—C₁₋₆ alkyl.

The term “halogen”, “halide” or “halo” refers to fluorine, chlorine,bromine, and/or iodine.

The term “optionally substituted” is intended to mean that a group orsubstituent, such as an alkyl, alkenyl, alkynyl, cycloalkyl, aryl,aralkyl, heteroaryl, or heterocyclyl group, may be substituted with oneor more substituents Q, each of which is independently selected from,e.g., (a) oxo (═O), halo, cyano (—CN), nitro (—NO₂), andpentafluorosulfanyl (—SF₅); (b) C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl, heteroaryl, heteroaralkyl,heterocyclyl, and heterocyclylalkyl, each of which is further optionallysubstituted with one or more, in one embodiment, one, two, three, orfour, substituents Q^(a); and (c) —B(R^(a))OR^(d), —B(OR^(a))OR^(d),—C(O)R^(a), —C(O)OR^(a), —C(O)NR^(b)R^(c), —C(NR^(a))NR^(b)R^(c),OR^(a), —OC(O)R^(a), —OC(O)OR^(a), —OC(O)NR^(b)R^(c),—OC(═NR^(a))NR^(b)R^(c), —OS(O)R^(a), —OS(O)₂R^(a), —OS(O)NR^(b)R^(c),—OS(O)₂NR^(b)R^(c), —NR^(a)C(O)R^(d), —NR^(a)C(O)OR^(d),—NR^(a)C(O)NR^(b)R^(c), —NR^(a)C(═NR^(d))NR^(b)R^(c), —NR^(a)S(O)R^(d),—NR^(a)S(O)₂R^(d), —NR^(a)S(O)NR^(b)R^(c), —NR^(a)S(O)₂NR^(b)R^(c),—P(O)R^(a)R^(d), —P(O)(OR^(a))R^(d), —P(O)(OR^(a))(OR^(d)), —SR^(a),—S(O)R^(a), —S(O)₂R^(a), —S(O)NR^(b)R^(c), and —S(O)₂NR^(b)R^(c),wherein each R^(a), R^(b), R^(c), and R^(d) is independently (i)hydrogen; (ii) C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl,C₆₋₁₄ aryl, C₇₋₁₅ aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, orheterocyclylalkyl, each optionally substituted with one or more, in oneembodiment, one, two, three, or four, substituents Q^(a); or (iii) R^(b)and R^(c) together with the N atom to which they are attached formheteroaryl or heterocyclyl, optionally substituted with one or more, inone embodiment, one, two, three, or four, substituents Q^(a). As usedherein, all groups that can be substituted are “optionally substituted,”unless otherwise specified.

In one embodiment, each Q^(a) is independently selected from the groupconsisting of (a) oxo, cyano, halo, nitro, and pentafluorosulfanyl(—SF₅); and (b) C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl, heteroaryl, heteroaralkyl,heterocyclyl, and heterocyclylalkyl; and (c) —B(R^(e))OR^(g),—B(OR^(e))OR^(g), —C(O)R^(e), —C(O)OR^(e), —C(O)NR^(f)R^(g),—C(NR^(e))NR^(f)R^(g), —OR^(e), —OC(O)R^(e), —OC(O)OR^(e),—OC(O)NR^(f)R^(g), —OC(═NR^(e))NR^(f)R^(g), —OS(O)R^(e), —OS(O)₂R^(e),—OS(O)NR^(f)R^(g), —OS(O)₂NR^(f)R^(g), —NR^(f)R^(g), —NR^(e)C(O)R^(h),—NR^(e)C(O)OR^(h), —NR^(e)C(O)NR^(f)R^(g), —NR^(e)C(═NR^(h))NR^(f)R^(g),—NR^(e)S(O)R^(h), —NR^(e)S(O)₂R^(h), —NR^(e)S(O)NR^(f)R^(g),—NR^(e)S(O)₂NR^(f)R^(g), —P(O)R^(e)R^(h), —P(O)(OR^(e))R^(h),—P(O)(OR^(e))(OR^(h)), —SR^(e), —S(O)R^(e), —S(O)₂R^(e),—S(O)NR^(f)R^(g), and —S(O)₂NR^(f)R^(g); wherein each R^(e), R^(f),R^(g), and R^(h) is independently (i) hydrogen, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl,heteroaryl, heteroaralkyl, heterocyclyl, or heterocyclylalkyl; or (ii)R^(f) and R^(g) together with the N atom to which they are attached formheteroaryl or heterocyclyl.

The terms “optically active” and “enantiomerically active” refer to acollection of molecules, which has an enantiomeric excess of no lessthan about 50%, no less than about 70%, no less than about 80%, no lessthan about 90%, no less than about 91%, no less than about 92%, no lessthan about 93%, no less than about 94%, no less than about 95%, no lessthan about 96%, no less than about 97%, no less than about 98%, no lessthan about 99%, no less than about 99.5%, or no less than about 99.8%.In certain embodiments, the compound comprises about 95% or more of oneenantiomer and about 5% or less of the other enantiomer based on thetotal weight of the racemate in question.

In describing an optically active compound, the prefixes R and S areused to denote the absolute configuration of the molecule about itschiral center(s). The (+) and (−) are used to denote the opticalrotation of the compound, that is, the direction in which a plane ofpolarized light is rotated by the optically active compound. The (−)prefix indicates that the compound is levorotatory, that is, thecompound rotates the plane of polarized light to the left orcounterclockwise. The (+) prefix indicates that the compound isdextrorotatory, that is, the compound rotates the plane of polarizedlight to the right or clockwise. However, the sign of optical rotation,(+) and (−), is not related to the absolute configuration of themolecule, R and S.

The term “isotopic variant” refers to a compound that contains anunnatural proportion of an isotope at one or more of the atoms thatconstitute such a compound. In certain embodiments, an “isotopicvariant” of a compound contains unnatural proportions of one or moreisotopes, including, but not limited to, hydrogen (¹H), deuterium (²H),tritium (³H), carbon-11 (¹¹C), carbon-12 (¹²C), carbon-13 (¹³C),carbon-14 (¹⁴C), nitrogen-13 (¹³N), nitrogen-14 (¹⁴N), nitrogen-15(¹⁵N), oxygen-14 (¹⁴O), oxygen-15 (¹⁵O), oxygen-16 (¹⁶O), oxygen-17(¹⁷O), oxygen-18 (¹⁸O) fluorine-17 (¹⁷F), fluorine-18 (¹⁸F),phosphorus-31 (³¹P), phosphorus-32 (³²P), phosphorus-33 (³³P), sulfur-32(³²S), sulfur-33 (³³S), sulfur-34 (³⁴S), sulfur-35 (³⁵S), sulfur-36(³⁶S), chlorine-35 (³⁵Cl), chlorine-36 (³⁶Cl), chlorine-37 (³⁷Cl),bromine-79 (⁷⁹Br), bromine-81 (⁸¹Br), iodine-123 (¹²³I) iodine-125(¹²⁵I) iodine-127 (¹²⁷I) iodine-129 (¹²⁹I) and iodine-131 (¹³¹I). Incertain embodiments, an “isotopic variant” of a compound is in a stableform, that is, non-radioactive. In certain embodiments, an “isotopicvariant” of a compound contains unnatural proportions of one or moreisotopes, including, but not limited to, hydrogen (¹H), deuterium (²H),carbon-12 (¹²C), carbon-13 (¹³C), nitrogen-14 (¹⁴N), nitrogen-15 (¹⁵N),oxygen-16 (¹⁶O) oxygen-17 (¹⁷O), oxygen-18 (¹⁸O) fluorine-17 (¹⁷F),phosphorus-31 (³¹P), sulfur-32 (³²S), sulfur-33 (³³S), sulfur-34 (³⁴S),sulfur-36 (³⁶S), chlorine-35 (³⁵Cl), chlorine-37 (³⁷Cl), bromine-79(⁷⁹Br), bromine-81 (⁸¹Br), and iodine-127 (¹²⁷I). In certainembodiments, an “isotopic variant” of a compound is in an unstable form,that is, radioactive. In certain embodiments, an “isotopic variant” of acompound contains unnatural proportions of one or more isotopes,including, but not limited to, tritium (³H), carbon-11 (¹¹C), carbon-14(¹⁴C), nitrogen-13 (¹³N), oxygen-14 (¹⁴O), oxygen-15 (¹⁵O), fluorine-18(¹⁸F), phosphorus-32 (³²P), phosphorus-33 (³³P), sulfur-35 (³⁵S),chlorine-36 (³⁶Cl), iodine-123 (¹²³I) iodine-125 (¹²⁵I), iodine-129(¹²⁹I), and iodine-131 (¹³¹I). It will be understood that, in a compoundas provided herein, any hydrogen can be ²H, as example, or any carboncan be ¹³C, as example, or any nitrogen can be ¹⁵N, as example, and anyoxygen can be ¹⁸O, as example, where feasible according to the judgmentof one of skill in the art. In certain embodiments, an “isotopicvariant” of a compound contains a unnatural proportion of deuterium.

The term “solvate” refers to a complex or aggregate formed by one ormore molecules of a solute, e.g., a compound provided herein, and one ormore molecules of a solvent, which present in a stoichiometric ornon-stoichiometric amount. Suitable solvents include, but are notlimited to, water, MeOH, ethanol, n-propanol, isopropanol, and aceticacid. In certain embodiments, the solvent is pharmaceuticallyacceptable. In one embodiment, the complex or aggregate is in acrystalline form. In another embodiment, the complex or aggregate is ina noncrystalline form. Where the solvent is water, the solvate is ahydrate. Examples of hydrates include, but are not limited to, ahemihydrate, monohydrate, dihydrate, trihydrate, tetrahydrate, andpentahydrate.

The term “naturally occurring” or “native” when used in connection withbiological materials such as nucleic acid molecules, polypeptides, hostcells, and the like, refers to materials which are found in nature andare not manipulated by man. Similarly, “non-naturally occurring” or“non-native” refers to a material that is not found in nature or thathas been structurally modified or synthesized by man.

The term “RC kinase” refers to regulated in COPD kinase or a variantthereof. RC kinase variants include proteins substantially homologous toa native RC kinase, i.e., proteins having one or more naturally ornon-naturally occurring amino acid deletions, insertions, orsubstitutions (e.g., RC kinase derivatives, homologs and fragments), ascompared to the amino acid sequence of a native RC kinase. The aminoacid sequence of a RC kinase variant is at least about 80% identical, atleast about 90% identical, or at least about 95% identical to a nativeRC kinase. Some examples of RC kinases are disclosed in U.S. Pat. No.7,829,685, the disclosure of which is incorporated herein by referencein its entirety.

The terms “RC kinase-mediated disorder, disease, or condition” and “adisorder, disease, or condition mediated by RC kinase” refer to adisorder, disease, or condition, characterized by abnormal ordysregulated, e.g., less than or greater than normal, RC kinaseactivity. Abnormal RC kinase functional activity might arise as theresult of RC kinase overexpression in cells, expression of RC kinase incells which normally do not express RC kinase, or dysregulation due toconstitutive activation, caused, for example, by a mutation in RCkinase. A RC kinase-mediated disorder, disease, or condition may becompletely or partially mediated by abnormal or dysregulated RC kinaseactivity. In particular, a RC kinase-mediated disorder, disease, orcondition is one in which modulation of a RC kinase activity results insome effect on the underlying disorder, disease, or condition, e.g., aRC kinase inhibitor results in some improvement in at least some ofpatients being treated.

The phrase “a stereoisomer, enantiomer, mixture of enantiomers, mixtureof diastereomers, or isotopic variant thereof; or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof” has the samemeaning as the phrase “a stereoisomer, enantiomer, mixture ofenantiomers, mixture of diastereomers, or isotopic variant of thecompound referenced therein; a pharmaceutically acceptable salt,solvate, hydrate, or prodrug of the compound referenced therein; or apharmaceutically acceptable salt, solvate, hydrate, or prodrug of astereoisomer, enantiomer, mixture of enantiomers, mixture ofdiastereomers, or isotopic variant of the compound referenced therein.”

Compounds

In one embodiment, provided herein is a 3,5-diaminopyrazole of FormulaI:

or a stereoisomer, enantiomer, mixture of enantiomers, mixture ofdiastereomers, or isotopic variant thereof; or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof; wherein:

R¹ is C₆₋₁₄ aryl, heteroaryl, or heterocyclyl;

R² and R³ are each independently C₁₋₆ alkyl or C₃₋₁₀ cycloalkyl;

wherein each alkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl isoptionally substituted with one or more substituents Q, where each Q isindependently selected from halo, C₁₋₆ alkyl, heteroaryl, andheterocyclyl, each of which is further optionally substituted with oneor more C₁₋₆ alkyl;

with the proviso that the compound is not3-((3-chlorophenyl)amino)-5-((4-hydroxy-3,5-dimethylbenzyl)amino)-1H-pyrazole-4-carboxamide.

In another embodiment, provided herein is a 3,5-diaminopyrazole ofFormula I:

or a stereoisomer, enantiomer, mixture of enantiomers, mixture ofdiastereomers, or isotopic variant thereof; or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof; wherein:

R¹ is C₆₋₁₄ aryl, heteroaryl, or heterocyclyl;

R² and R³ are each independently C₁₋₆ alkyl or C₃₋₁₀ cycloalkyl;

wherein each alkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl isoptionally substituted with one or more substituents Q, where each Q isindependently selected from halo, amino, aminosulfonyl, C₁₋₆ alkyl, C₁₋₆alkoxy, alkylamido, cyano, aryl, heteroaryl, and heterocyclyl, each ofwhich is further optionally substituted with one or more C₁₋₆ alkyl,halo, cyano, oxo, aralkyl, dialkylamino, arylamido, heterocyclyl,heterocyclylalkyl, or heterocyclylcarbonyl;

with the proviso that the compound is not3-((3-chlorophenyl)amino)-5-((4-hydroxy-3,5-dimethylbenzyl)amino)-1H-pyrazole-4-carboxamide.

In another embodiment, provided herein is a compound of Formula I, or astereoisomer, enantiomer, mixture of enantiomers, mixture ofdiastereomers, or isotopic variant thereof; or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof; wherein:

R¹ is C₆₋₁₄ aryl, heteroaryl, or heterocyclyl; each of which isoptionally substituted with one or more substituents Q, where each Q isindependently selected from halo, C₁₋₆ alkyl, heteroaryl, andheterocyclyl, each of which is further optionally substituted with oneor more, in one embodiment, one, two, three, four, or five C₁₋₆ alkyl;and

R² and R³ are each C₁₋₆ alkyl;

with the proviso that the compound is not3-((3-chlorophenyl)amino)-5-((4-hydroxy-3,5-dimethylbenzyl)amino)-1H-pyrazole-4-carboxamide.

In another embodiment, provided herein is a compound of Formula I, or astereoisomer, enantiomer, mixture of enantiomers, mixture ofdiastereomers, or isotopic variant thereof; or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof; wherein:

R¹ is C₆₋₁₄ aryl, heteroaryl, or heterocyclyl; each of which isoptionally substituted with one or more substituents Q, where each Q isindependently selected from halo, C₁₋₆ alkyl, C₁₋₆ alkoxy, alkylamido,amino, sulfonamide, cyano, aryl, heteroaryl, and heterocyclyl, each ofwhich is further optionally substituted with one or more, in oneembodiment, one, two, three, four, or five, groups selected from halo,cyano, oxo, aralkyl, dialkylamino, arylamido, heterocyclyl,heterocyclylalkyl, heteroaryl, and heterocyclylcarbonyl;

R² and R³ are each C₁₋₆ alkyl;

with the proviso that the compound is not3-((3-chlorophenyl)amino)-5-((4-hydroxy-3,5-dimethylbenzyl)amino)-1H-pyrazole-4-carboxamide.

In another embodiment, provided herein is a compound of Formula I, or astereoisomer, enantiomer, mixture of enantiomers, mixture ofdiastereomers, or isotopic variant thereof; or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof; wherein:

R¹ is phenyl or pyridinyl; each of which is optionally substituted withone or more substituents Q;

R² and R³ are each C₁₋₆ alkyl; and

Q is as defined herein;

with the proviso that the compound is not3-((3-chlorophenyl)amino)-5-((4-hydroxy-3,5-dimethylbenzyl)amino)-1H-pyrazole-4-carboxamide.

In yet another embodiment, provided herein is a compound of Formula I,or a stereoisomer, enantiomer, mixture of enantiomers, mixture ofdiastereomers, or isotopic variant thereof; or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof; wherein:

R¹ is C₆₋₁₄ aryl, heteroaryl, or heterocyclyl; each of which isoptionally substituted with one or more substituents Q, where each Q isindependently selected from fluoro, chloro, bromo, iodo, methyl,morpholinyl, dimethylmorpholinyl, pyrrolyl, isopropylpiperazinyl,methylpiperazinyl, pyridinyl, and benzylpiperazinyl;

R² and R³ are each C₁₋₆ alkyl;

with the proviso that the compound is not3-((3-chlorophenyl)amino)-5-((4-hydroxy-3,5-dimethylbenzyl)amino)-1H-pyrazole-4-carboxamide.

In yet another embodiment, provided herein is a compound of Formula I,or a stereoisomer, enantiomer, mixture of enantiomers, mixture ofdiastereomers, or isotopic variant thereof; or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof; wherein:

R¹ is C₆₋₁₄ aryl, heteroaryl, or heterocyclyl; each of which isoptionally substituted with one or more substituents Q, where each Q isindependently selected from fluoro, chloro, bromo, iodo, cyano, amino,aminosulfonyl, methyl, methoxy, morpholinyl, dimethylmorpholinyl,pyrrolyl, isopropylpiperazinyl, methylpiperazinyl, pyridinyl,benzylpiperazinyl, phenyl, imidazolyl, methoxy, tert-butyl, indazolyl,methylpiperidinyl, (pyrrolidinecarbonyl)piperazinyl, flouropiperidinyl,dimethylpyranyl, piperidinyl, benzyl, 1,1-dioxidothiomorpholino,pyrrolidinylmethyl, morpholinomethyl, dimethylamino, oxazolyl,pyrazolyl, (piperidinecarbonyl)piperazinyl, acetamido,(pyrimidinyl)piperizinyl, piperidinylmethyl, thiomorpholinyl,fluorophenylamido, methoxyphenylamido, isopropylpiperidinyl,cyanomethyl, (trifluoromethyl)phenylamido, and oxomorpholinyl;

R² and R³ are each C₁₋₆ alkyl;

with the proviso that the compound is not3-((3-chlorophenyl)amino)-5-((4-hydroxy-3,5-dimethylbenzyl)amino)-1H-pyrazole-4-carboxamide.

In still another embodiment, provided herein is a compound of Formula I,or a stereoisomer, enantiomer, mixture of enantiomers, mixture ofdiastereomers, or isotopic variant thereof; or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof; wherein:

R¹ is 3-methyl-4-morpholinophenyl, 3-chloro-4-morpholinophenyl,4-morpholinophenyl, 4-(2,6-dimethylmorpholino)phenyl,2-morpholino-3-chloropyridin-5-yl, 4-(1H-pyrrol-1-yl)phenyl,2-morpholinopyridin-5-yl, 4-(4-isopropylpiperazin-1-yl)phenyl,4-(pyridin-2-yl)phenyl, 4-(4-methylpiperazin-1-yl)phenyl,5-morpholinopyridin-2-yl, 2-morpholino-3-methylpyridin-5-yl,2-(4-isopropylpiperazin-1-yl)-3-methylpyridin-5-yl,2-(4-methylpiperazin-1-yl)-3-methylpyridin-5-yl,3-chloro-4-(2,6-dimethylmorpholino)phenyl, 4-(pyridin-3-yl)phenyl, or3-chloro-4-(4-isopropylpiperazin-1-yl)phenyl;

R² and R³ are each methyl;

with the proviso that the compound is not3-((3-chlorophenyl)amino)-5-((4-hydroxy-3,5-dimethylbenzyl)amino)-1H-pyrazole-4-carboxamide.

In still another embodiment, provided herein is a compound of Formula I,or a stereoisomer, enantiomer, mixture of enantiomers, mixture ofdiastereomers, or isotopic variant thereof; or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof; wherein:

R¹ is 3-methyl-4-morpholinophenyl, 3-chloro-4-morpholinophenyl,4-morpholinophenyl, 4-(2,6-dimethylmorpholino)phenyl,2-morpholino-3-chloropyridin-5-yl, 4-(1H-pyrrol-1-yl)phenyl,2-morpholinopyridin-5-yl, 4-(4-isopropylpiperazin-1-yl)phenyl,4-(pyridin-2-yl)phenyl, 4-(4-methylpiperazin-1-yl)phenyl,5-morpholinopyridin-2-yl, 2-morpholino-3-methylpyridin-5-yl,2-(4-isopropylpiperazin-1-yl)-3-methylpyridin-5-yl,2-(4-methylpiperazin-1-yl)-3-methylpyridin-5-yl,3-chloro-4-(2,6-dimethylmorpholino)phenyl, 4-(pyridin-3-yl)phenyl,3-chloro-4-(4-isopropylpiperazin-1-yl)phenyl, 1,1′-biphenyl,4-(1H-imidazol-1-yl)phenyl, 4-methoxyphenyl, 4-tert-butylphenyl,1H-indazol-5-yl, 4-(4-methyl-[1,4′-bipiperidin]-1′-yl)phenyl,4-(4-(pyrrolidine-1-carbonyl)piperazin-1-yl)phenyl,4-(4-fluoropiperidin-1-yl)phenyl,6-(2,6-dimethyltetrahydro-2H-pyran-4-yl)pyridin-3-yl,4-(piperidin-1-yl)phenyl. 3-chloro-4-(2,6-dimethylmorpholino)phenyl,3-methyl-4-(4-methylpiperazin-1-yl)phenyl,3-methyl-4-(piperidin-1-yl)phenyl,4-(4-benzylpiperazin-1-yl)-3-methylphenyl,4-(1,1-dioxidothiomorpholino)phenyl,(5-(piperidin-1-yl)pyridine-2-yl)phenyl,4-(4-chloropiperidin-1-yl)phenyl, 4-(pyrrolidin-1-ylmethyl)phenyl,4-(4-(dimethylamino)piperidin-1-yl)phenyl, 3-fluoro-4-morpholinophenyl,4-(oxazol-5-yl)phenyl,4-(4-(morpholine-4-carbonyl)piperazin-1-yl)phenyl, 3-acetamidophenyl,3-chloro-4-(4-methylpiperazin-1-yl)phenyl, 4-fluorophenyl,3-cyanophenyl, 4-(4-(pyrimidin-2-yl)piperazin-1-yl)phenyl,4-(piperidin-1-ylmethyl)phenyl, 4-thiomorpholinophenyl, 4-aminophenyl,4-(aminosulfonyl)phenyl,2-(4-(pyrrolidin-1-yl)piperidin-1-yl)pyridin-5-yl,4-(dimethylamino)phenyl, 4-(morpholinomethyl)phenyl. 2-methoxyphenyl,4-(4-fluorophenylamido)phenyl, 4-(4,5-dihydro-1H-pyrazol-3-yl)phenyl,4-(2-methoxyphenylamido)phenyl, 4-(3-methoxyphenylamido)phenyl,4-(4-methoxyphenylamido)phenyl, 4-(4-isopropylpiperidin-1-yl)phenyl4-(3-oxomorpholinyl)phenyl, 4-(1H-pyrazol-1-yl)phenyl,4-(2-cyanomethyl)phenyl, 4-((4-trifluoromethyl)phenylamido)phenyl, or4-(4-methylpiperidin-1-yl)phenyl;

R² and R³ are each methyl;

with the proviso that the compound is not3-((3-chlorophenyl)amino)-5-((4-hydroxy-3,5-dimethylbenzyl)amino)-1H-pyrazole-4-carboxamide.

In another embodiment, provided herein is a 3,5-diaminopyrazole ofFormula II:

or a stereoisomer, enantiomer, mixture of enantiomers, mixture ofdiastereomers, or isotopic variant thereof; or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof; wherein:

R² and R³ are each independently C₁₋₆ alkyl or C₃₋₁₀ cycloalkyl;

wherein each alkyl or cycloalkyl is optionally substituted with one ormore halo;

each R⁴ is independently selected from halo, C₁₋₆ alkyl, C₇₋₁₅ aralkyl,heterocyclyl, each of which is optionally substituted with one or moreC₁₋₆ alkyl;

wherein X and Y are each independently N or CH; and

n is 0, 1, 2, 3, 4, or 5;

with the proviso that the compound is not3-((3-chlorophenyl)amino)-5-((4-hydroxy-3,5-dimethylbenzyl)amino)-1H-pyrazole-4-carboxamide.

In another embodiment, provided herein is a 3,5-diaminopyrazole ofFormula II:

or a stereoisomer, enantiomer, mixture of enantiomers, mixture ofdiastereomers, or isotopic variant thereof; or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof; wherein:

R² and R³ are each independently C₁₋₆ alkyl or C₃₋₁₀ cycloalkyl;

wherein each alkyl or cycloalkyl is optionally substituted with one ormore halo;

each R⁴ is independently selected from halo, alkylamido, cyano, C₁₋₆alkyl, C₁₋₆ alkoxy, aryl, C₇₋₁₅ aralkyl, heterocyclyl, and heteroaryl,each of which is optionally substituted with one or more halo, C₁₋₆alkyl, aryl, C₇₋₁₅ aralkyl, heterocyclyl, dialkylamino, ordialkylaminocarbonyl;

wherein X and Y are each independently N or CH; and

n is 0, 1, 2, 3, 4, or 5;

In another embodiment, provided herein is a 3,5-diaminopyrazole ofFormula II:

or a stereoisomer, enantiomer, mixture of enantiomers, mixture ofdiastereomers, or isotopic variant thereof; or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof; wherein:

R² and R³ are each independently C₁₋₆ alkyl or C₃₋₁₀ cycloalkyl;

wherein each alkyl or cycloalkyl is optionally substituted with one ormore halo;

each R⁴ is independently selected from halo, amino, aminosulfonyl,alkylamido, arylamido, cyano, C₁₋₆ alkyl, C₁₋₆ alkoxy, aryl, C₇₋₁₅aralkyl, heterocyclyl, and heteroaryl, each of which is optionallysubstituted with one or more halo, cyano, oxo, C₁₋₆ alkyl, aryl, C₇₋₁₅aralkyl, heterocyclyl, oxo, dialkylamino, or dialkylaminocarbonyl;

wherein X and Y are each independently N or CH; and

n is 0, 1, 2, 3, 4, or 5;

In another embodiment, provided herein is a 3,5-diaminopyrazole ofFormula II-a:

or a stereoisomer, enantiomer, mixture of enantiomers, mixture ofdiastereomers, or isotopic variant thereof; or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof; wherein:

R² and R³ are each independently C₁₋₆ alkyl or C₃₋₁₀ cycloalkyl;

wherein each alkyl or cycloalkyl is optionally substituted with one ormore halo;

each R⁴ is independently selected from halo, C₁₋₆ alkyl, heteroaryl, andheterocyclyl, each of which is optionally substituted with one or moreC₁₋₆ alkyl; and

n is 0, 1, 2, 3, 4, or 5;

with the proviso that the compound is not3-((3-chlorophenyl)amino)-5-((4-hydroxy-3,5-dimethylbenzyl)amino)-1H-pyrazole-4-carboxamide.

In another embodiment, provided herein is a 3,5-diaminopyrazole ofFormula II-a:

or a stereoisomer, enantiomer, mixture of enantiomers, mixture ofdiastereomers, or isotopic variant thereof; or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof; wherein:

R² and R³ are each independently C₁₋₆ alkyl or C₃₋₁₀ cycloalkyl;

wherein each alkyl or cycloalkyl is optionally substituted with one ormore halo;

each R⁴ is independently selected from halo, alkylamido, arylamido,amino, aminosulfonyl, cyano, C₁₋₆ alkyl, C₁₋₆ alkoxy, aryl, C₇-15aralkyl, heterocyclyl, heterocyclylalkyl, and heteroaryl, each of whichis optionally substituted with one or more halo, cyano, oxo, C₁₋₆ alkyl,aryl, C₇₋₁₅ aralkyl, heterocyclyl, dialkylamino, ordialkylaminocarbonyl; and

n is 0, 1, 2, 3, 4, or 5;

with the proviso that the compound is not3-((3-chlorophenyl)amino)-5-((4-hydroxy-3,5-dimethylbenzyl)amino)-1H-pyrazole-4-carboxamide.

In another embodiment, provided herein is a 3,5-diaminopyrazole ofFormula II-b:

or a stereoisomer, enantiomer, mixture of enantiomers, mixture ofdiastereomers, or isotopic variant thereof; or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof; wherein:

R² and R³ are each independently C₁₋₆ alkyl or C₃₋₁₀ cycloalkyl;

wherein each alkyl or cycloalkyl is optionally substituted with one ormore halo;

each R⁴ is independently selected from halo, C₁₋₆ alkyl, heteroaryl, andheterocyclyl, each of which is optionally substituted with one or moreC₁₋₆ alkyl; and

n is 0, 1, 2, 3, or 4.

In another embodiment, provided herein is a 3,5-diaminopyrazole ofFormula II-c:

or a stereoisomer, enantiomer, mixture of enantiomers, mixture ofdiastereomers, or isotopic variant thereof; or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof; wherein:

R² and R³ are each independently C₁₋₆ alkyl or C₃₋₁₀ cycloalkyl;

wherein each alkyl or cycloalkyl is optionally substituted with one ormore halo;

each R⁴ is independently selected from halo, C₁₋₆ alkyl, heteroaryl, andheterocyclyl, each of which is optionally substituted with one or moreC₁₋₆ alkyl; and

n is 0, 1, 2, 3, or 4.

In another embodiment, provided herein is a 3,5-diaminopyrazole ofFormula II-c:

or a stereoisomer, enantiomer, mixture of enantiomers, mixture ofdiastereomers, or isotopic variant thereof; or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof; wherein:

R² and R³ are each independently C₁₋₆ alkyl or C₃₋₁₀ cycloalkyl;

wherein each alkyl or cycloalkyl is optionally substituted with one ormore halo;

each R⁴ is independently selected from halo, C₁₋₆ alkyl, heteroaryl, andheterocyclyl, each of which is optionally substituted with one or moreC₁₋₆ alkyl or heterocyclyl; and

n is 0, 1, 2, 3, or 4.

The groups, R¹, R², R³, R⁴, Q, and n in formulae described herein,including Formulae I, II, II-a, II-b, and II-c, are further definedherein. All combinations of the embodiments provided herein for suchgroups are within the scope of this disclosure.

In certain embodiments, R¹ is C₆₋₁₄ aryl, optionally substituted withone or more substituents Q. In certain embodiments, R¹ is C₆₋₁₄ aryl,optionally substituted with one or more substituents Q, wherein each Qindependently selected from halo, C₁₋₆ alkyl, heteroaryl, andheterocyclyl, where the alkyl, heteroaryl, and heterocyclyl are eachoptionally substituted with one or more C₁₋₆ alkyl. In certainembodiments, R¹ is C₆₋₁₄ aryl, optionally substituted with one or moresubstituents Q, wherein each substituent Q is independently selectedfrom chloro, methyl, piperazinyl, pyrrolyl, and morpholinyl, whereineach optionally substituted with one or more C₁₋₆ alkyl.

In certain embodiments, R¹ is C₆₋₁₄ aryl, optionally substituted withone or more substituents Q. In certain embodiments, R¹ is C₆₋₁₄ aryl,optionally substituted with one or more substituents Q, wherein each Qindependently selected from halo, alkylamido, cyano, C₁₋₆ alkyl, C₁₋₆alkoxy, heteroaryl, and heterocyclyl, where the alkyl, alkoxy,heteroaryl, and heterocyclyl are each optionally substituted with one ormore halo, C₁₋₆ alkyl, aralkyl, dialkylamino, heterocyclyl,heterocyclylalkyl, or heterocyclylcarbonyl. In certain embodiments, R¹is C₆₋₁₄ aryl, optionally substituted with one or more substituents Q,wherein each substituent Q is independently selected from chloro,fluoro, acetamido, cyano, methyl, methoxy, tert-butyl, imidazolyl,indazolyl, piperazinyl, piperidinyl, pyridinyl, pyrrolyl, morpholinyl,1,1-dioxidothiomorpholinyl, pyrrolidinylmethyl, morpholinomethyl,dimethylamino, oxazolyl, pyrazolyl, (piperidinecarbonyl)piperazinyl,acetamido, (pyrimidinyl)piperizinyl, piperidinylmethyl, thiomorpholinyl,fluorophenylamido, methoxyphenylamido, isopropylpiperidinyl,cyanomethyl, (trifluoromethyl)phenylamido, and oxomorpholinyl, whereineach substituent Q optionally substituted with one or more halo, C₁₋₆alkyl, aryl, cyano, oxo, dialkylamino, heterocyclyl, andheterocyclylcarbonyl.

In certain embodiments, R¹ is phenyl, optionally substituted with one ormore substituents Q. In certain embodiments, R¹ is phenyl, optionallysubstituted with one, two, three, four, or five substituents Q. Incertain embodiments, R¹ is phenyl, optionally substituted with one, two,three, four, or five substituents Q, wherein each substituent Q isindependently selected from halo, C₁₋₆ alkyl, heteroaryl, andheterocyclyl, where the alkyl, heteroaryl, and heterocyclyl are eachoptionally substituted with one or more C₁₋₆ alkyl. In certainembodiments, R¹ is phenyl, optionally substituted with one, two, three,four, or five substituents Q, wherein each substituent Q isindependently selected from chloro, methyl, piperazinyl, morphoplinyl,wherein each optionally substituted with one or more C₁₋₆ alkyl. Incertain embodiments, R¹ is 3-methyl-4-morpholinophenyl,3-chloro-4-morpholinophenyl, 4-morpholinophenyl,4-(2,6-dimethylmorpholino)phenyl, 4-(1H-pyrrol-1-yl)phenyl,4-(4-isopropylpiperazin-1-yl)phenyl, 4-(pyridin-2-yl)phenyl,(4-methylpiperazin-1-yl)phenyl,3-chloro-4-(2,6-dimethylmorpholino)phenyl, 4-(pyridin-3-yl)phenyl, or3-chloro-4-(4-isopropylpiperazin-1-yl)phenyl.

In certain embodiments, R¹ is phenyl, optionally substituted with one ormore substituents Q. In certain embodiments, R¹ is phenyl, optionallysubstituted with one, two, three, four, or five substituents Q. Incertain embodiments, R¹ is phenyl, optionally substituted with one, two,three, four, or five substituents Q, wherein each substituent Q isindependently selected from halo, C₁₋₆ alkyl, heteroaryl, andheterocyclyl, halo, C₁₋₆ alkyl, C₁₋₆ alkoxy, heteroaryl, andheterocyclyl, where the alkyl, alkoxy, heteroaryl, and heterocyclyl areeach optionally substituted with one or more halo, C₁₋₆ alkyl, aralkyl,dialkylamino, heterocyclyl, heterocyclylalkyl, or heterocyclylcarbonyl.In certain embodiments, R¹ is phenyl, optionally substituted with one,two, three, four, or five substituents Q, wherein each substituent Q isindependently selected from chloro, fluoro, methyl, methoxy, tert-butyl,imidazolyl, indazolyl, piperazinyl, piperidinyl, pyridinyl, pyrrolyl,morpholinyl, and 1,1-dioxidothiomorpholinyl, wherein each substituent Qis optionally substituted with one or more halo, C₁₋₆ alkyl, aralkyl,heteroarylalkyl, heterocyclyl, or heterocylylcarbonyl. In certainembodiments, is 3-methyl-4-morpholinophenyl,3-chloro-4-morpholinophenyl, 4-morpholinophenyl,4-(2,6-dimethylmorpholino)phenyl, 4-(1H-pyrrol-1-yl)phenyl,4-(4-isopropylpiperazin-1-yl)phenyl, 4-(pyridin-2-yl)phenyl,4-(4-methylpiperazin-1-yl)phenyl,3-chloro-4-(2,6-dimethylmorpholino)phenyl, 4-(pyridin-3-yl)phenyl,3-chloro-4-(4-isopropylpiperazin-1-yl)phenyl, 1,1′-biphenyl,4-(1H-imidazol-1-yl)phenyl, 4-methoxyphenyl, 4-tert-butylphenyl,4-(4-methyl-[1,4′-bipiperidin]-1′-yl)phenyl,4-(4-(morpholine-4-carbonyl)piperazin-1-yl)phenyl,4-(4-fluoropiperidin-1-yl)phenyl, 4-(piperidin-1-yl)phenyl.3-chloro-4-(2,6-dimethylmorpholino)phenyl,3-methyl-4-(4-methylpiperazin-1-yl)phenyl,3-methyl-4-(piperidin-1-yl)phenyl,4-(4-benzylpiperazin-1-yl)-3-methylphenyl,4-(1,1-dioxidothiomorpholino)phenyl,(5-(piperidin-1-yl)pyridine-2-yl)phenyl,4-(4-chloropiperidin-1-yl)phenyl, 4-(pyrrolidin-1-ylmethyl)phenyl,4-(4-(dimethylamino)piperidin-1-yl)phenyl, 3-fluoro-4-morpholinophenyl,4-(oxazol-5-yl)phenyl,4-(4-(piperidine-1-carbonyl)piperazin-1-yl)phenyl, 3-acetamidophenyl,3-chloro-4-(4-methylpiperazin-1-yl)phenyl, 4-fluorophenyl,3-cyanophenyl, 4-(4-(pyrimidin-2-yl)piperazin-1-yl)phenyl,4-(piperidin-1-ylmethyl)phenyl, 4-thiomorpholinophenyl, 4-aminophenyl,4-(aminosulfonyl)phenyl, 4-(dimethylamino)phenyl,4-(morpholinomethyl)phenyl. 2-methoxyphenyl,4-(4-fluorophenylamido)phenyl, 4-(4,5-dihydro-1H-pyrazol-3-yl)phenyl,4-(2-methoxyphenylamido)phenyl, 4-(3-methoxyphenylamido)phenyl,4-(4-methoxyphenylamido)phenyl, 4-(4-isopropylpiperidin-1-yl)phenyl4-(3-oxomorpholinyl)phenyl, 4-(2-cyanomethyl)phenyl,4-((4-trifluoromethyl)phenylamido)phenyl, or4-(4-methylpiperidin-1-yl)phenyl.

In certain embodiments, R¹ is heteroaryl, optionally substituted withone or more substituents Q. In certain embodiments, R¹ is monocyclicheteroaryl, optionally substituted with one or more substituents Q. Incertain embodiments, R¹ is 5- or 6-membered heteroaryl, optionallysubstituted with one or more substituents Q. In certain embodiments, R¹is 5-membered heteroaryl, optionally substituted with one or moresubstituents Q. In certain embodiments, R¹ is 6-membered heteroaryl,optionally substituted with one or more substituents Q. In certainembodiments, R¹ is pyridinyl, optionally substituted with one or moresubstituents Q. In certain embodiments, R¹ is2-morpholino-3-chloropyridin-5-yl, 2-morpholinopyridin-5-yl,5-morpholinopyridin-2-yl, 2-morpholino-3-methylpyridin-5-yl,2-(4-isopropylpiperazin-1-yl)-3-methylpyridin-5-yl, or2-(4-methylpiperazin-1-yl)-3-methylpyridin-5-yl.

In certain embodiments, R¹ is heteroaryl, optionally substituted withone or more substituents Q. In certain embodiments, R¹ is monocyclicheteroaryl, optionally substituted with one or more substituents Q. R¹is bicyclic heteroaryl, optionally substituted with one or moresubstituents Q. In certain embodiments, R¹ is 5- or 6-memberedheteroaryl, optionally substituted with one or more substituents Q. Incertain embodiments, R¹ is 5-membered heteroaryl, optionally substitutedwith one or more substituents Q. In certain embodiments, R¹ is6-membered heteroaryl, optionally substituted with one or moresubstituents Q. In certain embodiments, R¹ is pyridinyl, optionallysubstituted with one or more substituents Q. In certain embodiments, R¹is 2-morpholino-3-chloropyridin-5-yl, 2-morpholinopyridin-5-yl,5-morpholinopyridin-2-yl, 2-morpholino-3-methylpyridin-5-yl,2-(4-isopropylpiperazin-1-yl)-3-methylpyridin-5-yl,2-(4-methylpiperazin-1-yl)-3-methylpyridin-5-yl, 1H-indazol-5-yl,6-(2,6-dimethyltetrahydro-2H-pyran-4-yl)pyridin-3-yl, or2-(4-(pyrrolidin-1-yl)piperidin-1-yl)pyridin-5-yl.

In certain embodiments, R² is C₁₋₆ alkyl, optionally substituted withone or more substituents Q. In certain embodiments, R² is C₃₋₁₀cycloalkyl, optionally substituted with one or more substituents Q. Incertain embodiments, R² is methyl.

In certain embodiments, R³ is C₁₋₆ alkyl, optionally substituted withone or more substituents Q. In certain embodiments, R³ is C₃₋₁₀cycloalkyl, optionally substituted with one or more substituents Q. Incertain embodiments, R³ is methyl.

In certain embodiments, R⁴ is halo. In certain embodiments, R⁴ isflouro, chloro, or bromo. In certain embodiments, R⁴ is C₁₋₆ alkyl. Incertain embodiments, R⁴ is heteroaryl, optionally substituted with oneor more C₁₋₆ alkyl. In certain embodiments, R⁴ is heterocyclyl,optionally substituted with one or more C₁₋₆ alkyl.

In certain embodiments, R⁴ is halo. In certain embodiments, R⁴ isflouro, chloro, or bromo. In certain embodiments, R⁴ is cyano. Incertain embodiments, R⁴ is alkylamido. In certain embodiments, R⁴ isacetamido. In certain embodiments, R⁴ is arylamido. In certainembodiments, R⁴ is amino. In certain embodiments, R⁴ is dialkylamino. Incertain embodiments, R⁴ is aminosulfonyl. In certain embodiments, R⁴ isC₁₋₆ alkyl. In certain embodiments, R⁴ is C₁₋₆ alkyl substituted withone or more cyano. In certain embodiments, R⁴ is heteroaryl, optionallysubstituted with one or more C₁₋₆ alkyl. In certain embodiments, R⁴ isheterocyclyl, optionally substituted with one or more C₁₋₆ alkyl. Incertain embodiments, R⁴ is heterocyclyl, optionally substituted with oneor more oxo.

In certain embodiments, n is 0. In certain embodiments, n is 1. Incertain embodiments, n is 2. In certain embodiments, n is 3. In certainembodiments, n is 4. In certain embodiments, n is 5.

In one embodiment, the compound provided herein is selected from:

and stereoisomers, enantiomers, mixtures of enantiomers, mixtures ofdiastereomers, and isotopic variants thereof; and pharmaceuticallyacceptable salts, solvates, hydrates, and prodrugs thereof.

In one embodiment, the compound provided herein is selected from:

and stereoisomers, enantiomers, mixtures of enantiomers, mixtures ofdiastereomers, and isotopic variants thereof; and pharmaceuticallyacceptable salts, solvates, hydrates, and prodrugs thereof.

The compounds provided herein are intended to encompass all possiblestereoisomers, unless a particular stereochemistry is specified. Wherethe compound provided herein contains an alkenyl or alkenylene group,the compound may exist as one or a mixture of geometric cis/trans (orZ/E) isomers. Where structural isomers are interconvertible, thecompound may exist as a single tautomer or a mixture of tautomers. Thiscan take the form of proton tautomerism in the compound that contains,for example, an imino, keto, or oxime group; or so-called valencetautomerism in the compound that contain an aromatic moiety. It followsthat a single compound may exhibit more than one type of isomerism.

The compounds provided herein may be enantiomerically pure, such as asingle enantiomer or a single diastereomer, or be stereoisomericmixtures, such as mixture of enantiomers, e.g., a racemic mixture of twoenantiomers; or a mixture of two or more diastereomers. As such, one ofskill in the art will recognize that administration of a compound in its(R) form is equivalent, for compounds that undergo epimerization invivo, to administration of the compound in its (S) form. Conventionaltechniques for the preparation/isolation of individual enantiomersinclude synthesis from a suitable optically pure precursor, asymmetricsynthesis from achiral starting materials, or resolution of anenantiomeric mixture, for example, chiral chromatography,recrystallization, resolution, diastereomeric salt formation, orderivatization into diastereomeric adducts followed by separation.

When the compound provided herein contains an acidic or basic moiety, itmay also be provided as a pharmaceutically acceptable salt. See, Bergeet al., J. Pharm. Sci. 1977, 66, 1-19; and Handbook of PharmaceuticalSalts, Properties, and Use; Stahl and Wermuth, Ed.; Wiley-VCH and VHCA:Zurich, Switzerland, 2002.

Suitable acids for use in the preparation of pharmaceutically acceptablesalts include, but are not limited to, acetic acid, 2,2-dichloroaceticacid, acylated amino acids, adipic acid, alginic acid, ascorbic acid,L-aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoicacid, boric acid, (+)-camphoric acid, camphorsulfonic acid,(+)-(1S)-camphor-10-sulfonic acid, capric acid, caproic acid, caprylicacid, cinnamic acid, citric acid, cyclamic acid, cyclohexanesulfamicacid, dodecyl sulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonicacid, 2-hydroxy-ethanesulfonic acid, formic acid, fumaric acid,galactaric acid, gentisic acid, glucoheptonic acid, D-gluconic acid,D-glucuronic acid, L-glutamic acid, α-oxoglutaric acid, glycolic acid,hippuric acid, hydrobromic acid, hydrochloric acid, hydroiodic acid,(+)-L-lactic acid, (±)-DL-lactic acid, lactobionic acid, lauric acid,maleic acid, (−)-L-malic acid, malonic acid, (±)-DL-mandelic acid,methanesulfonic acid, naphthalene-2-sulfonic acid,naphthalene-1,5-disulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinicacid, nitric acid, oleic acid, orotic acid, oxalic acid, palmitic acid,pamoic acid, perchloric acid, phosphoric acid, L-pyroglutamic acid,saccharic acid, salicylic acid, 4-amino-salicylic acid, sebacic acid,stearic acid, succinic acid, sulfuric acid, tannic acid, (+)-L-tartaricacid, thiocyanic acid, p-toluenesulfonic acid, undecylenic acid, andvaleric acid.

Suitable bases for use in the preparation of pharmaceutically acceptablesalts, including, but not limited to, inorganic bases, such as magnesiumhydroxide, calcium hydroxide, potassium hydroxide, zinc hydroxide, orsodium hydroxide; and organic bases, such as primary, secondary,tertiary, and quaternary, aliphatic and aromatic amines, includingL-arginine, benethamine, benzathine, choline, deanol, diethanolamine,diethylamine, dimethylamine, dipropylamine, diisopropylamine,2-(diethylamino)-ethanol, ethanolamine, ethylamine, ethylenediamine,isopropylamine, N-methyl-glucamine, hydrabamine, 1H-imidazole, L-lysine,morpholine, 4-(2-hydroxyethyl)-morpholine, methylamine, piperidine,piperazine, propylamine, pyrrolidine, 1-(2-hydroxyethyl)-pyrrolidine,pyridine, quinuclidine, quinoline, isoquinoline, secondary amines,triethanolamine, trimethylamine, triethylamine, N-methyl-D-glucamine,2-amino-2-(hydroxymethyl)-1,3-propanediol, and tromethamine.

The compound provided herein may also be provided as a prodrug, which isa functional derivative of the compound, for example, of Formula I, andis readily convertible into the parent compound in vivo. Prodrugs areoften useful because, in some situations, they may be easier toadminister than the parent compound. They may, for instance, bebioavailable by oral administration whereas the parent compound is not.The prodrug may also have enhanced solubility in pharmaceuticalcompositions over the parent compound. A prodrug may be converted intothe parent drug by various mechanisms, including enzymatic processes andmetabolic hydrolysis. See, Harper, Progress in Drug Research 1962, 4,221-294; Morozowich et al. in Design of Biopharmaceutical Propertiesthrough Prodrugs and Analogs; Roche Ed., APHA Acad. Pharm. Sci.: 1977;Gangwar et al., Des. Biopharm. Prop. Prodrugs Analogs, 1977, 409-421;Bundgaard, Arch. Pharm. Chem. 1979, 86, 1-39; Farquhar et al., J. Pharm.Sci. 1983, 72, 324-325; Wernuth in Drug Design: Fact or Fantasy; Jolleset al. Eds.; Academic Press: London, 1984; pp 47-72; Design of Prodrugs;Bundgaard et al. Eds.; Elsevier: 1985; Fleisher et al., Methods Enzymol.1985, 112, 360-381; Stella et al., Drugs 1985, 29, 455-473;Bioreversible Carriers in Drug in Drug Design, Theory and Application;Roche Ed.; APHA Acad. Pharm. Sci.: 1987; Bundgaard, Controlled DrugDelivery 1987, 17, 179-96; Waller et al., Br. J. Clin. Pharmac. 1989,28, 497-507; Balant et al., Eur. J. Drug Metab. Pharmacokinet. 1990, 15,143-53; Freeman et al., J. Chem. Soc., Chem. Commun. 1991, 875-877;Bundgaard, Adv. Drug Delivery Rev. 1992, 8, 1-38; Nathwani and Wood,Drugs 1993, 45, 866-94; Friis and Bundgaard, Eur. J. Pharm. Sci. 1996,4, 49-59; Fleisher et al., Adv. Drug Delivery Rev. 1996, 19, 115-130;Sinhababu and Thakker, Adv. Drug Delivery Rev. 1996, 19, 241-273;Taylor, Adv. Drug Delivery Rev. 1996, 19, 131-148; Gaignault et al.,Pract. Med. Chem. 1996, 671-696; Browne, Clin. Neuropharmacol. 1997, 20,1-12; Valentino and Borchardt, Drug Discovery Today 1997, 2, 148-155;Pauletti et al., Adv. Drug. Delivery Rev. 1997, 27, 235-256; Mizen etal., Pharm. Biotech. 1998, 11, 345-365; Wiebe and Knaus, Adv. DrugDelivery Rev. 1999, 39, 63-80; Tan et al., Adv. Drug Delivery Rev. 1999,39, 117-151; Balimane and Sinko, Adv. Drug Delivery Rev. 1999, 39,183-209; Wang et al., Curr. Pharm. Design 1999, 5, 265-287; Han et al.,AAPS Pharmsci. 2000, 2, 1-11; Asgharnej ad in Transport Processes inPharmaceutical Systems; Amidon et al., Eds.; Marcell Dekker: 2000; pp185-218; Sinha et al., Pharm. Res. 2001, 18, 557-564; Anand et al.,Expert Opin. Biol. Ther. 2002, 2, 607-620; Rao, Resonace 2003, 19-27;Sloan et al., Med. Res. Rev. 2003, 23, 763-793; Patterson et al., Curr.Pharm. Des. 2003, 9, 2131-2154; Hu, IDrugs 2004, 7, 736-742; Robinson etal., Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 14527-14532; Erion et al.,J. Pharmacol. Exp. Ther. 2005, 312, 554-560; Fang et al., Curr. DrugDiscov. Technol. 2006, 3, 211-224; Stanczak et al., Pharmacol. Rep.2006, 58, 599-613; Sloan et al., Pharm. Res. 2006, 23, 2729-2747; Stellaet al., Adv. Drug Deliv. Rev. 2007, 59, 677-694; Gomes et al., Molecules2007, 12, 2484-2506; Krafz et al., Chem Med Chem 2008, 3, 20-53; Rautioet al., AAPS J. 2008, 10, 92-102; Rautio et al., Nat. Rev. Drug. Discov.2008, 7, 255-270; Pavan et al., Molecules, 2008, 13, 1035-1065; Sandroset al., Molecules 2008, 13, 1156-1178; Singh et al., Curr. Med. Chem.2008, 15, 1802-1826; Onishi et al., Molecules, 2008, 13, 2136-2155;Huttunen et al., Curr. Med. Chem. 2008, 15, 2346-2365; and Serafin etal., Mini Rev. Med. Chem. 2009, 9, 481-497.

Methods of Synthesis

The compounds provided herein can be prepared, isolated, or obtained byany method known to one of skill in the art; and the following examplesare only representative and do not exclude other related methods andprocedures. See also, U.S. patent application Ser. Nos. 13/830,486 and13/830,712, the disclosure of each of which is incorporated herein byreference in its entirety.

In one embodiment, for example, a compound of Formula I can be preparedas shown in Scheme I. Compound I-1 is first converted to compound I-2 byreacting with carbon disulfide and dimethylsulfate. Compound I-2 thenreacts with an amine, such as R¹NH₂, to form compound I-3.Alternatively, Compound I-3 may be made by reacting an isothiocyanate(R¹NCS) with Compound I-1 and methyl iodide. Subsequently, compound I-3reacts with hydrazine to form compound I-4, which is then treated with acarbonyl compound, such as 4-hydroxy-3,5-dimethylbenzaldehyde, to form acompound of Formula I, e.g., compound I-5. The imine group of compoundI-5 can be reduced with a reducing agent, e.g., sodium borohydride(NaBH₄) or sodium cyanoborohydride (NaB(CN)H₃), to form compound I-6.

In another embodiment, for example, a compound of Formula I can beprepared as shown in Scheme II. Compound I-7 reacts an amine, such asR²NH₂, to form compound I-8. Alternatively, compound I-8 can be made byreacting an isothiocyanate (R²NCS) with malononitrile and methyl iodide.Compound I-8 is then treated with hydrazine to form compound I-9. Thecyano group of compound I-9 is converted to aminocarbonyl, e.g., byreacting with hydrogen peroxide. Compound I-4 can then be converted intocompounds I-5 and I-6 as described herein.

Pharmaceutical Compositions

Provided herein are pharmaceutical compositions comprising a compoundprovided herein, e.g., a compound of Formula I, as an active ingredient,including a stereoisomer, enantiomer, mixture of enantiomers, mixture ofdiastereomers, or isotopic variant thereof; or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof; and apharmaceutically excipient.

Suitable excipients are well known to those skilled in the art, andnon-limiting examples of suitable excipients are provided herein.Whether a particular excipient is suitable for incorporation into apharmaceutical composition or dosage form depends on a variety offactors well known in the art, including, but not limited to, the methodof administration. For example, oral dosage forms such as tablets maycontain excipients not suited for use in parenteral dosage forms. Thesuitability of a particular excipient may also depend on the specificactive ingredients in the dosage form. For example, the decomposition ofsome active ingredients may be accelerated by some excipients such aslactose, or when exposed to water. Active ingredients that compriseprimary or secondary amines are particularly susceptible to suchaccelerated decomposition. Consequently, provided herein arepharmaceutical compositions and dosage forms that contain little, ifany, lactose, or other mono- or di-saccharides. As used herein, the term“lactose-free” means that the amount of lactose present, if any, isinsufficient to substantially increase the degradation rate of an activeingredient. In one embodiment, lactose-free compositions comprise anactive ingredient provided herein, a binder/filler, and a lubricant. Inanother embodiment, lactose-free dosage forms comprise an activeingredient, microcrystalline cellulose, pre-gelatinized starch, andmagnesium stearate.

The compound provided herein may be administered alone, or incombination with one or more other compounds provided herein. Thepharmaceutical compositions that comprise a compound provided herein,e.g., a compound of Formula I, including a stereoisomer, enantiomer,mixture of enantiomers, mixture of diastereomers, or isotopic variantthereof; or a pharmaceutically acceptable salt, solvate, hydrate, orprodrug thereof, can be formulated in various dosage forms for oral,parenteral, and topical administration. The pharmaceutical compositionscan also be formulated as modified release dosage forms, includingdelayed-, extended-, prolonged-, sustained-, pulsatile-, controlled-,accelerated-, fast-, targeted-, programmed-release, and gastricretention dosage forms. These dosage forms can be prepared according toconventional methods and techniques known to those skilled in the art(see, Remington: The Science and Practice of Pharmacy, supra;Modified-Release Drug Delivery Technology, 2nd ed.; Rathbone et al.,Eds.; Marcel Dekker, Inc.: New York, N.Y., 2008).

In one embodiment, the pharmaceutical compositions are provided in adosage form for oral administration, which comprise a compound providedherein, e.g., a compound of Formula I, including a stereoisomer,enantiomer, mixture of enantiomers, mixture of diastereomers, orisotopic variant thereof; or a pharmaceutically acceptable salt,solvate, hydrate, or prodrug thereof; and one or more pharmaceuticallyacceptable excipients.

In another embodiment, the pharmaceutical compositions are provided in adosage form for parenteral administration, which comprise a compoundprovided herein, e.g., a compound of Formula I, including astereoisomer, enantiomer, mixture of enantiomers, mixture ofdiastereomers, or isotopic variant thereof; or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof; and one or morepharmaceutically acceptable excipients.

In yet another embodiment, the pharmaceutical compositions are providedin a dosage form for topical administration, which comprise a compoundprovided herein, e.g., a compound of Formula I, including astereoisomer, enantiomer, mixture of enantiomers, mixture ofdiastereomers, or isotopic variant thereof; or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof; and one or morepharmaceutically acceptable excipients.

The pharmaceutical compositions provided herein can be provided in aunit-dosage form or multiple-dosage form. A unit-dosage form, as usedherein, refers to physically discrete a unit suitable for administrationto a human and animal subject, and packaged individually as is known inthe art. Each unit-dose contains a predetermined quantity of an activeingredient(s) sufficient to produce the desired therapeutic effect, inassociation with the required pharmaceutical carriers or excipients.Examples of a unit-dosage form include an ampoule, syringe, andindividually packaged tablet and capsule. For example, a 100 mg unitdose contains about 100 mg of an active ingredient in a packaged tabletor capsule. A unit-dosage form may be administered in fractions ormultiples thereof. A multiple-dosage form is a plurality of identicalunit-dosage forms packaged in a single container to be administered insegregated unit-dosage form. Examples of a multiple-dosage form includea vial, bottle of tablets or capsules, or bottle of pints or gallons.

The pharmaceutical compositions provided herein can be administered atonce, or multiple times at intervals of time. It is understood that theprecise dosage and duration of treatment may vary with the age, weight,and condition of the patient being treated, and may be determinedempirically using known testing protocols or by extrapolation from invivo or in vitro test or diagnostic data. It is further understood thatfor any particular individual, specific dosage regimens should beadjusted over time according to the individual need and the professionaljudgment of the person administering or supervising the administrationof the formulations.

A. Oral Administration

The pharmaceutical compositions provided herein for oral administrationcan be provided in solid, semisolid, or liquid dosage forms for oraladministration. As used herein, oral administration also includesbuccal, lingual, and sublingual administration. Suitable oral dosageforms include, but are not limited to, tablets, fastmelts, chewabletablets, capsules, pills, strips, troches, lozenges, pastilles, cachets,pellets, medicated chewing gum, bulk powders, effervescent ornon-effervescent powders or granules, oral mists, solutions, emulsions,suspensions, wafers, sprinkles, elixirs, and syrups. In addition to theactive ingredient(s), the pharmaceutical compositions can contain one ormore pharmaceutically acceptable carriers or excipients, including, butnot limited to, binders, fillers, diluents, disintegrants, wettingagents, lubricants, glidants, coloring agents, dye-migration inhibitors,sweetening agents, flavoring agents, emulsifying agents, suspending anddispersing agents, preservatives, solvents, non-aqueous liquids, organicacids, and sources of carbon dioxide.

Binders or granulators impart cohesiveness to a tablet to ensure thetablet remaining intact after compression. Suitable binders orgranulators include, but are not limited to, starches, such as cornstarch, potato starch, and pre-gelatinized starch (e.g., STARCH 1500);gelatin; sugars, such as sucrose, glucose, dextrose, molasses, andlactose; natural and synthetic gums, such as acacia, alginic acid,alginates, extract of Irish moss, panwar gum, ghatti gum, mucilage ofisabgol husks, carboxymethylcellulose, methylcellulose,polyvinylpyrrolidone (PVP), Veegum, larch arabogalactan, powderedtragacanth, and guar gum; celluloses, such as ethyl cellulose, celluloseacetate, carboxymethyl cellulose calcium, sodium carboxymethylcellulose, methyl cellulose, hydroxyethylcellulose (HEC),hydroxypropylcellulose (HPC), hydroxypropyl methyl cellulose (HPMC);microcrystalline celluloses, such as AVICEL-PH-101, AVICEL-PH-103,AVICEL RC-581, AVICEL-PH-105 (FMC Corp., Marcus Hook, Pa.); and mixturesthereof. Suitable fillers include, but are not limited to, talc, calciumcarbonate, microcrystalline cellulose, powdered cellulose, dextrates,kaolin, mannitol, silicic acid, sorbitol, starch, pre-gelatinizedstarch, and mixtures thereof. The amount of a binder or filler in thepharmaceutical compositions provided herein varies upon the type offormulation, and is readily discernible to those of ordinary skill inthe art. The binder or filler may be present from about 50 to about 99%by weight in the pharmaceutical compositions provided herein.

Suitable diluents include, but are not limited to, dicalcium phosphate,calcium sulfate, lactose, sorbitol, sucrose, inositol, cellulose,kaolin, mannitol, sodium chloride, dry starch, and powdered sugar.Certain diluents, such as mannitol, lactose, sorbitol, sucrose, andinositol, when present in sufficient quantity, can impart properties tosome compressed tablets that permit disintegration in the mouth bychewing. Such compressed tablets can be used as chewable tablets. Theamount of a diluent in the pharmaceutical compositions provided hereinvaries upon the type of formulation, and is readily discernible to thoseof ordinary skill in the art.

Suitable disintegrants include, but are not limited to, agar; bentonite;celluloses, such as methylcellulose and carboxymethylcellulose; woodproducts; natural sponge; cation-exchange resins; alginic acid; gums,such as guar gum and Veegum HV; citrus pulp; cross-linked celluloses,such as croscarmellose; cross-linked polymers, such as crospovidone;cross-linked starches; calcium carbonate; microcrystalline cellulose,such as sodium starch glycolate; polacrilin potassium; starches, such ascorn starch, potato starch, tapioca starch, and pre-gelatinized starch;clays; aligns; and mixtures thereof. The amount of a disintegrant in thepharmaceutical compositions provided herein varies upon the type offormulation, and is readily discernible to those of ordinary skill inthe art. The pharmaceutical compositions provided herein may containfrom about 0.5 to about 15% or from about 1 to about 5% by weight of adisintegrant.

Suitable lubricants include, but are not limited to, calcium stearate;magnesium stearate; mineral oil; light mineral oil; glycerin; sorbitol;mannitol; glycols, such as glycerol behenate and polyethylene glycol(PEG); stearic acid; sodium lauryl sulfate; talc; hydrogenated vegetableoil, including peanut oil, cottonseed oil, sunflower oil, sesame oil,olive oil, corn oil, and soybean oil; zinc stearate; ethyl oleate; ethyllaureate; agar; starch; lycopodium; silica or silica gels, such asAEROSIL® 200 (W.R. Grace Co., Baltimore, Md.) and CAB-O-SIL® (Cabot Co.of Boston, Mass.); and mixtures thereof. The pharmaceutical compositionsprovided herein may contain about 0.1 to about 5% by weight of alubricant.

Suitable glidants include, but are not limited to, colloidal silicondioxide, CAB-O-SIL® (Cabot Co. of Boston, Mass.), and asbestos-freetalc. Suitable coloring agents include, but are not limited to, any ofthe approved, certified, water soluble FD&C dyes, and water insolubleFD&C dyes suspended on alumina hydrate, and color lakes and mixturesthereof. A color lake is the combination by adsorption of awater-soluble dye to a hydrous oxide of a heavy metal, resulting in aninsoluble form of the dye. Suitable flavoring agents include, but arenot limited to, natural flavors extracted from plants, such as fruits,and synthetic blends of compounds which produce a pleasant tastesensation, such as peppermint and methyl salicylate. Suitable sweeteningagents include, but are not limited to, sucrose, lactose, mannitol,syrups, glycerin, and artificial sweeteners, such as saccharin andaspartame. Suitable emulsifying agents include, but are not limited to,gelatin, acacia, tragacanth, bentonite, and surfactants, such aspolyoxyethylene sorbitan monooleate (TWEEN® 20), polyoxyethylenesorbitan monooleate 80 (TWEEN® 80), and triethanolamine oleate. Suitablesuspending and dispersing agents include, but are not limited to, sodiumcarboxymethylcellulose, pectin, tragacanth, Veegum, acacia, sodiumcarbomethylcellulose, hydroxypropyl methylcellulose, andpolyvinylpyrrolidone. Suitable preservatives include, but are notlimited to, glycerin, methyl and propylparaben, benzoic add, sodiumbenzoate and alcohol. Suitable wetting agents include, but are notlimited to, propylene glycol monostearate, sorbitan monooleate,diethylene glycol monolaurate, and polyoxyethylene lauryl ether.Suitable solvents include, but are not limited to, glycerin, sorbitol,ethyl alcohol, and syrup. Suitable non-aqueous liquids utilized inemulsions include, but are not limited to, mineral oil and cottonseedoil. Suitable organic acids include, but are not limited to, citric andtartaric acid. Suitable sources of carbon dioxide include, but are notlimited to, sodium bicarbonate and sodium carbonate.

It should be understood that many carriers and excipients may serve aplurality of functions, even within the same formulation.

The pharmaceutical compositions provided herein for oral administrationcan be provided as compressed tablets, tablet triturates, chewablelozenges, rapidly dissolving tablets, multiple compressed tablets, orenteric-coating tablets, sugar-coated, or film-coated tablets.Enteric-coated tablets are compressed tablets coated with substancesthat resist the action of stomach acid but dissolve or disintegrate inthe intestine, thus protecting the active ingredients from the acidicenvironment of the stomach. Enteric-coatings include, but are notlimited to, fatty acids, fats, phenyl salicylate, waxes, shellac,ammoniated shellac, and cellulose acetate phthalates. Sugar-coatedtablets are compressed tablets surrounded by a sugar coating, which maybe beneficial in covering up objectionable tastes or odors and inprotecting the tablets from oxidation. Film-coated tablets arecompressed tablets that are covered with a thin layer or film of awater-soluble material. Film coatings include, but are not limited to,hydroxyethylcellulose, sodium carboxymethylcellulose, polyethyleneglycol 4000, and cellulose acetate phthalate. Film coating imparts thesame general characteristics as sugar coating. Multiple compressedtablets are compressed tablets made by more than one compression cycle,including layered tablets, and press-coated or dry-coated tablets.

The tablet dosage forms can be prepared from the active ingredient inpowdered, crystalline, or granular forms, alone or in combination withone or more carriers or excipients described herein, including binders,disintegrants, controlled-release polymers, lubricants, diluents, and/orcolorants. Flavoring and sweetening agents are especially useful in theformation of chewable tablets and lozenges.

The pharmaceutical compositions provided herein for oral administrationcan be provided as soft or hard capsules, which can be made fromgelatin, methylcellulose, starch, or calcium alginate. The hard gelatincapsule, also known as the dry-filled capsule (DFC), consists of twosections, one slipping over the other, thus completely enclosing theactive ingredient. The soft elastic capsule (SEC) is a soft, globularshell, such as a gelatin shell, which is plasticized by the addition ofglycerin, sorbitol, or a similar polyol. The soft gelatin shells maycontain a preservative to prevent the growth of microorganisms. Suitablepreservatives are those as described herein, including methyl- andpropyl-parabens, and sorbic acid. The liquid, semisolid, and soliddosage forms provided herein may be encapsulated in a capsule. Suitableliquid and semisolid dosage forms include solutions and suspensions inpropylene carbonate, vegetable oils, or triglycerides. Capsulescontaining such solutions can be prepared as described in U.S. Pat. Nos.4,328,245; 4,409,239; and 4,410,545. The capsules may also be coated asknown by those of skill in the art in order to modify or sustaindissolution of the active ingredient.

The pharmaceutical compositions provided herein for oral administrationcan be provided in liquid and semisolid dosage forms, includingemulsions, solutions, suspensions, elixirs, and syrups. An emulsion is atwo-phase system, in which one liquid is dispersed in the form of smallglobules throughout another liquid, which can be oil-in-water orwater-in-oil. Emulsions may include a pharmaceutically acceptablenon-aqueous liquid or solvent, emulsifying agent, and preservative.Suspensions may include a pharmaceutically acceptable suspending agentand preservative. Aqueous alcoholic solutions may include apharmaceutically acceptable acetal, such as a di(lower alkyl) acetal ofa lower alkyl aldehyde, e.g., acetaldehyde diethyl acetal; and awater-miscible solvent having one or more hydroxyl groups, such aspropylene glycol and ethanol. Elixirs are clear, sweetened, andhydroalcoholic solutions. Syrups are concentrated aqueous solutions of asugar, for example, sucrose, and may also contain a preservative. For aliquid dosage form, for example, a solution in a polyethylene glycol maybe diluted with a sufficient quantity of a pharmaceutically acceptableliquid carrier, e.g., water, to be measured conveniently foradministration.

Other useful liquid and semisolid dosage forms include, but are notlimited to, those containing the active ingredient(s) provided herein,and a dialkylated mono- or poly-alkylene glycol, including,1,2-dimethoxymethane, diglyme, triglyme, tetraglyme, polyethyleneglycol-350-dimethyl ether, polyethylene glycol-550-dimethyl ether,polyethylene glycol-750-dimethyl ether, wherein 350, 550, and 750 referto the approximate average molecular weight of the polyethylene glycol.These formulations can further comprise one or more antioxidants, suchas butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA),propyl gallate, vitamin E, hydroquinone, hydroxycoumarins, ethanolamine,lecithin, cephalin, ascorbic acid, malic acid, sorbitol, phosphoricacid, bisulfite, sodium metabisulfite, thiodipropionic acid and itsesters, and dithiocarbamates.

The pharmaceutical compositions provided herein for oral administrationcan be also provided in the forms of liposomes, micelles, microspheres,or nanosystems. Micellar dosage forms can be prepared as described inU.S. Pat. No. 6,350,458.

The pharmaceutical compositions provided herein for oral administrationcan be provided as non-effervescent or effervescent, granules andpowders, to be reconstituted into a liquid dosage form. Pharmaceuticallyacceptable carriers and excipients used in the non-effervescent granulesor powders may include diluents, sweeteners, and wetting agents.Pharmaceutically acceptable carriers and excipients used in theeffervescent granules or powders may include organic acids and a sourceof carbon dioxide.

Coloring and flavoring agents can be used in all of the above dosageforms.

The pharmaceutical compositions provided herein for oral administrationcan be formulated as immediate or modified release dosage forms,including delayed-, sustained, pulsed-, controlled, targeted-, andprogrammed-release forms.

B. Parenteral Administration

The pharmaceutical compositions provided herein can be administeredparenterally by injection, infusion, or implantation, for local orsystemic administration. Parenteral administration, as used herein,include intravenous, intraarterial, intraperitoneal, intrathecal,intraventricular, intraurethral, intrasternal, intracranial,intramuscular, intrasynovial, intravesical, and subcutaneousadministration.

The pharmaceutical compositions provided herein for parenteraladministration can be formulated in any dosage forms that are suitablefor parenteral administration, including solutions, suspensions,emulsions, micelles, liposomes, microspheres, nanosystems, and solidforms suitable for solutions or suspensions in liquid prior toinjection. Such dosage forms can be prepared according to conventionalmethods known to those skilled in the art of pharmaceutical science(see, Remington: The Science and Practice of Pharmacy, supra).

The pharmaceutical compositions intended for parenteral administrationcan include one or more pharmaceutically acceptable carriers andexcipients, including, but not limited to, aqueous vehicles,water-miscible vehicles, non-aqueous vehicles, antimicrobial agents orpreservatives against the growth of microorganisms, stabilizers,solubility enhancers, isotonic agents, buffering agents, antioxidants,local anesthetics, suspending and dispersing agents, wetting oremulsifying agents, complexing agents, sequestering or chelating agents,cryoprotectants, lyoprotectants, thickening agents, pH adjusting agents,and inert gases.

Suitable aqueous vehicles include, but are not limited to, water,saline, physiological saline or phosphate buffered saline (PBS), sodiumchloride injection, Ringers injection, isotonic dextrose injection,sterile water injection, dextrose and lactated Ringers injection.Suitable non-aqueous vehicles include, but are not limited to, fixedoils of vegetable origin, castor oil, corn oil, cottonseed oil, oliveoil, peanut oil, peppermint oil, safflower oil, sesame oil, soybean oil,hydrogenated vegetable oils, hydrogenated soybean oil, and medium-chaintriglycerides of coconut oil, and palm seed oil. Suitable water-misciblevehicles include, but are not limited to, ethanol, 1,3-butanediol,liquid polyethylene glycol (e.g., polyethylene glycol 300 andpolyethylene glycol 400), propylene glycol, glycerin,N-methyl-2-pyrrolidone, N,N-dimethylacetamide, and dimethyl sulfoxide.

Suitable antimicrobial agents or preservatives include, but are notlimited to, phenols, cresols, mercurials, benzyl alcohol, chlorobutanol,methyl and propyl p-hydroxybenzoates, thimerosal, benzalkonium chloride(e.g., benzethonium chloride), methyl- and propyl-parabens, and sorbicacid. Suitable isotonic agents include, but are not limited to, sodiumchloride, glycerin, and dextrose. Suitable buffering agents include, butare not limited to, phosphate and citrate. Suitable antioxidants arethose as described herein, including bisulfate and sodium metabisulfite.Suitable local anesthetics include, but are not limited to, procainehydrochloride. Suitable suspending and dispersing agents are those asdescribed herein, including sodium carboxymethylcelluose, hydroxypropylmethylcellulose, and polyvinylpyrrolidone. Suitable emulsifying agentsare those described herein, including polyoxyethylene sorbitanmonolaurate, polyoxyethylene sorbitan monooleate 80, and triethanolamineoleate. Suitable sequestering or chelating agents include, but are notlimited to EDTA. Suitable pH adjusting agents include, but are notlimited to, sodium hydroxide, hydrochloric acid, citric acid, and lacticacid. Suitable complexing agents include, but are not limited to,cyclodextrins, including α-cyclodextrin, β-cyclodextrin,hydroxypropyl-β-cyclodextrin, sulfobutylether-β-cyclodextrin, andsulfobutylether 7-β-cyclodextrin (CAPTISOL®, CyDex, Lenexa, Kans.).

When the pharmaceutical compositions provided herein are formulated formultiple dosage administration, the multiple dosage parenteralformulations must contain an antimicrobial agent at bacteriostatic orfungistatic concentrations. All parenteral formulations must be sterile,as known and practiced in the art.

In one embodiment, the pharmaceutical compositions for parenteraladministration are provided as ready-to-use sterile solutions. Inanother embodiment, the pharmaceutical compositions are provided assterile dry soluble products, including lyophilized powders andhypodermic tablets, to be reconstituted with a vehicle prior to use. Inyet another embodiment, the pharmaceutical compositions are provided asready-to-use sterile suspensions. In yet another embodiment, thepharmaceutical compositions are provided as sterile dry insolubleproducts to be reconstituted with a vehicle prior to use. In stillanother embodiment, the pharmaceutical compositions are provided asready-to-use sterile emulsions.

The pharmaceutical compositions provided herein for parenteraladministration can be formulated as immediate or modified release dosageforms, including delayed-, sustained, pulsed-, controlled, targeted-,and programmed-release forms.

The pharmaceutical compositions provided herein for parenteraladministration can be formulated as a suspension, solid, semi-solid, orthixotropic liquid, for administration as an implanted depot. In oneembodiment, the pharmaceutical compositions provided herein aredispersed in a solid inner matrix, which is surrounded by an outerpolymeric membrane that is insoluble in body fluids but allows theactive ingredient in the pharmaceutical compositions diffuse through.

Suitable inner matrixes include, but are not limited to,polymethylmethacrylate, polybutyl-methacrylate, plasticized orunplasticized polyvinylchloride, plasticized nylon, plasticizedpolyethylene terephthalate, natural rubber, polyisoprene,polyisobutylene, polybutadiene, polyethylene, ethylene-vinyl acetatecopolymers, silicone rubbers, polydimethylsiloxanes, silicone carbonatecopolymers, hydrophilic polymers, such as hydrogels of esters of acrylicand methacrylic acid, collagen, cross-linked polyvinyl alcohol, andcross-linked partially hydrolyzed polyvinyl acetate.

Suitable outer polymeric membranes include but are not limited to,polyethylene, polypropylene, ethylene/propylene copolymers,ethylene/ethyl acrylate copolymers, ethylene/vinyl acetate copolymers,silicone rubbers, polydimethyl siloxanes, neoprene rubber, chlorinatedpolyethylene, polyvinylchloride, vinyl chloride copolymers with vinylacetate, vinylidene chloride, ethylene and propylene, ionomerpolyethylene terephthalate, butyl rubber epichlorohydrin rubbers,ethylene/vinyl alcohol copolymer, ethylene/vinyl acetate/vinyl alcoholterpolymer, and ethylene/vinyloxyethanol copolymer.

C. Topical Administration

The pharmaceutical compositions provided herein can be administeredtopically to the skin, orifices, or mucosa. The topical administration,as used herein, includes (intra)dermal, conjunctival, intracorneal,intraocular, ophthalmic, auricular, transdermal, nasal, vaginal,urethral, respiratory, and rectal administration.

The pharmaceutical compositions provided herein can be formulated in anydosage forms that are suitable for topical administration for local orsystemic effect, including emulsions, solutions, suspensions, creams,gels, hydrogels, ointments, dusting powders, dressings, elixirs,lotions, suspensions, tinctures, pastes, foams, films, aerosols,irrigations, sprays, suppositories, bandages, and dermal patches. Thetopical formulation of the pharmaceutical compositions provided hereincan also comprise liposomes, micelles, microspheres, nanosystems, andmixtures thereof

Pharmaceutically acceptable carriers and excipients suitable for use inthe topical formulations provided herein include, but are not limitedto, aqueous vehicles, water-miscible vehicles, non-aqueous vehicles,antimicrobial agents or preservatives against the growth ofmicroorganisms, stabilizers, solubility enhancers, isotonic agents,buffering agents, antioxidants, local anesthetics, suspending anddispersing agents, wetting or emulsifying agents, complexing agents,sequestering or chelating agents, penetration enhancers,cryoprotectants, lyoprotectants, thickening agents, and inert gases.

The pharmaceutical compositions can also be administered topically byelectroporation, iontophoresis, phonophoresis, sonophoresis, ormicroneedle or needle-free injection, such as POWDERJECT™ (Chiron Corp.,Emeryville, Calif.), and BIOJECT™ (Bioject Medical Technologies Inc.,Tualatin, Oreg.).

The pharmaceutical compositions provided herein can be provided in theforms of ointments, creams, and gels. Suitable ointment vehicles includeoleaginous or hydrocarbon vehicles, including lard, benzoinated lard,olive oil, cottonseed oil, and other oils, white petrolatum;emulsifiable or absorption vehicles, such as hydrophilic petrolatum,hydroxystearin sulfate, and anhydrous lanolin; water-removable vehicles,such as hydrophilic ointment; water-soluble ointment vehicles, includingpolyethylene glycols of varying molecular weight; emulsion vehicles,either water-in-oil (W/O) emulsions or oil-in-water (O/W) emulsions,including cetyl alcohol, glyceryl monostearate, lanolin, and stearicacid (see, Remington: The Science and Practice of Pharmacy, supra).These vehicles are emollient but generally require addition ofantioxidants and preservatives.

Suitable cream base can be oil-in-water or water-in-oil. Suitable creamvehicles may be water-washable, and contain an oil phase, an emulsifier,and an aqueous phase. The oil phase is also called the “internal” phase,which is generally comprised of petrolatum and a fatty alcohol such ascetyl or stearyl alcohol. The aqueous phase usually, although notnecessarily, exceeds the oil phase in volume, and generally contains ahumectant. The emulsifier in a cream formulation may be a nonionic,anionic, cationic, or amphoteric surfactant.

Gels are semisolid, suspension-type systems. Single-phase gels containorganic macromolecules distributed substantially uniformly throughoutthe liquid carrier. Suitable gelling agents include, but are not limitedto, crosslinked acrylic acid polymers, such as carbomers,carboxypolyalkylenes, and CARBOPOL®; hydrophilic polymers, such aspolyethylene oxides, polyoxyethylene-polyoxypropylene copolymers, andpolyvinylalcohol; cellulosic polymers, such as hydroxypropyl cellulose,hydroxyethyl cellulose, hydroxypropyl methylcellulose, hydroxypropylmethylcellulose phthalate, and methylcellulose; gums, such as tragacanthand xanthan gum; sodium alginate; and gelatin. In order to prepare auniform gel, dispersing agents such as alcohol or glycerin can be added,or the gelling agent can be dispersed by trituration, mechanical mixing,and/or stirring.

The pharmaceutical compositions provided herein can be administeredrectally, urethrally, vaginally, or perivaginally in the forms ofsuppositories, pessaries, bougies, poultices or cataplasm, pastes,powders, dressings, creams, plasters, contraceptives, ointments,solutions, emulsions, suspensions, tampons, gels, foams, sprays, orenemas. These dosage forms can be manufactured using conventionalprocesses as described in Remington: The Science and Practice ofPharmacy, supra.

Rectal, urethral, and vaginal suppositories are solid bodies forinsertion into body orifices, which are solid at ordinary temperaturesbut melt or soften at body temperature to release the activeingredient(s) inside the orifices. Pharmaceutically acceptable carriersutilized in rectal and vaginal suppositories include bases or vehicles,such as stiffening agents, which produce a melting point in theproximity of body temperature, when formulated with the pharmaceuticalcompositions provided herein; and antioxidants as described herein,including bisulfite and sodium metabisulfite. Suitable vehicles include,but are not limited to, cocoa butter (theobroma oil), glycerin-gelatin,carbowax (polyoxyethylene glycol), spermaceti, paraffin, white andyellow wax, and appropriate mixtures of mono-, di- and triglycerides offatty acids, and hydrogels, such as polyvinyl alcohol, hydroxyethylmethacrylate, and polyacrylic acid. Combinations of the various vehiclescan also be used. Rectal and vaginal suppositories may be prepared bycompressing or molding. The typical weight of a rectal and vaginalsuppository is about 2 to about 3 g.

The pharmaceutical compositions provided herein can be administeredophthalmically in the forms of solutions, suspensions, ointments,emulsions, gel-forming solutions, powders for solutions, gels, ocularinserts, and implants.

The pharmaceutical compositions provided herein can be administeredintranasally or by inhalation to the respiratory tract. Thepharmaceutical compositions can be provided in the form of an aerosol orsolution for delivery using a pressurized container, pump, spray,atomizer, such as an atomizer using electrohydrodynamics to produce afine mist, or nebulizer, alone or in combination with a suitablepropellant, such as 1,1,1,2-tetrafluoroethane or1,1,1,2,3,3,3-heptafluoropropane. The pharmaceutical compositions canalso be provided as a dry powder for insufflation, alone or incombination with an inert carrier such as lactose or phospholipids; andnasal drops. For intranasal use, the powder can comprise a bioadhesiveagent, including chitosan or cyclodextrin.

Solutions or suspensions for use in a pressurized container, pump,spray, atomizer, or nebulizer can be formulated to contain ethanol,aqueous ethanol, or a suitable alternative agent for dispersing,solubilizing, or extending release of the active ingredient providedherein; a propellant as solvent; and/or a surfactant, such as sorbitantrioleate, oleic acid, or an oligolactic acid.

The pharmaceutical compositions provided herein can be micronized to asize suitable for delivery by inhalation, such as about 50 micrometersor less, or about 10 micrometers or less. Particles of such sizes can beprepared using a comminuting method known to those skilled in the art,such as spiral jet milling, fluid bed jet milling, supercritical fluidprocessing to form nanoparticles, high pressure homogenization, or spraydrying.

Capsules, blisters, and cartridges for use in an inhaler or insufflatorcan be formulated to contain a powder mix of the pharmaceuticalcompositions provided herein; a suitable powder base, such as lactose orstarch; and a performance modifier, such as l-leucine, mannitol, ormagnesium stearate. The lactose may be anhydrous or in the form of themonohydrate. Other suitable excipients or carriers include, but are notlimited to, dextran, glucose, maltose, sorbitol, xylitol, fructose,sucrose, and trehalose. The pharmaceutical compositions provided hereinfor inhaled/intranasal administration can further comprise a suitableflavor, such as menthol and levomenthol; and/or sweeteners, such assaccharin and saccharin sodium.

The pharmaceutical compositions provided herein for topicaladministration can be formulated to be immediate release or modifiedrelease, including delayed-, sustained-, pulsed-, controlled-, targeted,and programmed release.

D. Modified Release

The pharmaceutical compositions provided herein can be formulated as amodified release dosage form. As used herein, the term “modifiedrelease” refers to a dosage form in which the rate or place of releaseof the active ingredient(s) is different from that of an immediatedosage form when administered by the same route. Modified release dosageforms include, but are not limited to, delayed-, extended-, prolonged-,sustained-, pulsatile-, controlled-, accelerated- and fast-, targeted-,programmed-release, and gastric retention dosage forms. Thepharmaceutical compositions in modified release dosage forms can beprepared using a variety of modified release devices and methods knownto those skilled in the art, including, but not limited to, matrixcontrolled release devices, osmotic controlled release devices,multiparticulate controlled release devices, ion-exchange resins,enteric coatings, multilayered coatings, microspheres, liposomes, andcombinations thereof. The release rate of the active ingredient(s) canalso be modified by varying the particle sizes and polymorphorism of theactive ingredient(s).

Examples of modified release include, but are not limited to, thosedescribed in U.S. Pat. Nos. 3,845,770; 3,916,899; 3,536,809; 3,598,123;4,008,719; 5,674,533; 5,059,595; 5,591,767; 5,120,548; 5,073,543;5,639,476; 5,354,556; 5,639,480; 5,733,566; 5,739,108; 5,891,474;5,922,356; 5,958,458; 5,972,891; 5,980,945; 5,993,855; 6,045,830;6,087,324; 6,113,943; 6,197,350; 6,248,363; 6,264,970; 6,267,981;6,270,798; 6,375,987; 6,376,461; 6,419,961; 6,589,548; 6,613,358;6,623,756; 6,699,500; 6,793,936; 6,827,947; 6,902,742; 6,958,161;7,255,876; 7,416,738; 7,427,414; 7,485,322; Bussemer et al., Crit. Rev.Ther. Drug Carrier Syst. 2001, 18, 433-458; Modified-Release DrugDelivery Technology, 2nd ed.; Rathbone et al., Eds.; Marcel Dekker AG:2005; Maroni et al., Expert. Opin. Drug Deliv. 2005, 2, 855-871; Shi etal., Expert Opin. Drug Deliv. 2005, 2, 1039-1058; Polymers in DrugDelivery; Ijeoma et al., Eds.; CRC Press LLC: Boca Raton, Fla., 2006;Badawy et al., J. Pharm. Sci. 2007, 9, 948-959; Modified-Release DrugDelivery Technology, supra; Conway, Recent Pat. Drug Deliv. Formul.2008, 2, 1-8; Gazzaniga et al., Eur. J. Pharm. Biopharm. 2008, 68,11-18; Nagarwal et al., Curr. Drug Deliv. 2008, 5, 282-289; Gallardo etal., Pharm. Dev. Technol. 2008, 13, 413-423; Chrzanowski, AAPS Pharm SciTech. 2008, 9, 635-638; Chrzanowski, AAPS Pharm Sci Tech. 2008, 9,639-645; Kalantzi et al., Recent Pat. Drug Deliv. Formul. 2009, 3,49-63; Saigal et al., Recent Pat. Drug Deliv. Formul. 2009, 3, 64-70;and Roy et al., J. Control Release 2009, 134, 74-80.

1. Matrix Controlled Release Devices

The pharmaceutical compositions provided herein in a modified releasedosage form can be fabricated using a matrix controlled release deviceknown to those skilled in the art. See, Takada et al. in Encyclopedia ofControlled Drug Delivery; Mathiowitz Ed.; Wiley: 1999; Vol 2.

In certain embodiments, the pharmaceutical compositions provided hereinin a modified release dosage form is formulated using an erodible matrixdevice, which is water-swellable, erodible, or soluble polymers,including, but not limited to, synthetic polymers, and naturallyoccurring polymers and derivatives, such as polysaccharides andproteins.

Materials useful in forming an erodible matrix include, but are notlimited to, chitin, chitosan, dextran, and pullulan; gum agar, gumarabic, gum karaya, locust bean gum, gum tragacanth, carrageenans, gumghatti, guar gum, xanthan gum, and scleroglucan; starches, such asdextrin and maltodextrin; hydrophilic colloids, such as pectin;phosphatides, such as lecithin; alginates; propylene glycol alginate;gelatin; collagen; cellulosics, such as ethyl cellulose (EC),methylethyl cellulose (MEC), carboxymethyl cellulose (CMC), CMEC,hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), celluloseacetate (CA), cellulose propionate (CP), cellulose butyrate (CB),cellulose acetate butyrate (CAB), CAP, CAT, hydroxypropyl methylcellulose (HPMC), HPMCP, HPMCAS, hydroxypropyl methyl cellulose acetatetrimellitate (HPMCAT), and ethyl hydroxyethyl cellulose (EHEC);polyvinyl pyrrolidone; polyvinyl alcohol; polyvinyl acetate; glycerolfatty acid esters; polyacrylamide; polyacrylic acid; copolymers ofethacrylic acid or methacrylic acid (EUDRAGIT®, Rohm America, Inc.,Piscataway, N.J.); poly(2-hydroxyethyl-methacrylate); polylactides;copolymers of L-glutamic acid and ethyl-L-glutamate; degradable lacticacid-glycolic acid copolymers; poly-D-(−)-3-hydroxybutyric acid; andother acrylic acid derivatives, such as homopolymers and copolymers ofbutylmethacrylate, methyl methacrylate, ethyl methacrylate,ethylacrylate, (2-dimethylaminoethyl)methacrylate, and(trimethylaminoethyl)methacrylate chloride.

In certain embodiments, the pharmaceutical compositions provided hereinare formulated with a non-erodible matrix device. The activeingredient(s) is dissolved or dispersed in an inert matrix and isreleased primarily by diffusion through the inert matrix onceadministered. Materials suitable for use as a non-erodible matrix deviceinclude, but are not limited to, insoluble plastics, such aspolyethylene, polypropylene, polyisoprene, polyisobutylene,polybutadiene, polymethylmethacrylate, polybutylmethacrylate,chlorinated polyethylene, polyvinylchloride, methyl acrylate-methylmethacrylate copolymers, ethylene-vinyl acetate copolymers,ethylene/propylene copolymers, ethylene/ethyl acrylate copolymers, vinylchloride copolymers with vinyl acetate, vinylidene chloride, ethyleneand propylene, ionomer polyethylene terephthalate, butyl rubbers,epichlorohydrin rubbers, ethylene/vinyl alcohol copolymer,ethylene/vinyl acetate/vinyl alcohol terpolymer,ethylene/vinyloxyethanol copolymer, polyvinyl chloride, plasticizednylon, plasticized polyethylene terephthalate, natural rubber, siliconerubbers, polydimethylsiloxanes, and silicone carbonate copolymers;hydrophilic polymers, such as ethyl cellulose, cellulose acetate,crospovidone, and cross-linked partially hydrolyzed polyvinyl acetate;and fatty compounds, such as carnauba wax, microcrystalline wax, andtriglycerides.

In a matrix controlled release system, the desired release kinetics canbe controlled, for example, via the polymer type employed, the polymerviscosity, the particle sizes of the polymer and/or the activeingredient(s), the ratio of the active ingredient(s) versus the polymer,and other excipients or carriers in the compositions.

The pharmaceutical compositions provided herein in a modified releasedosage form can be prepared by methods known to those skilled in theart, including direct compression, dry or wet granulation followed bycompression, and melt-granulation followed by compression.

2. Osmotic Controlled Release Devices

The pharmaceutical compositions provided herein in a modified releasedosage form can be fabricated using an osmotic controlled releasedevice, including, but not limited to, one-chamber system, two-chambersystem, asymmetric membrane technology (AMT), and extruding core system(ECS). In general, such devices have at least two components: (a) a corewhich contains an active ingredient; and (b) a semipermeable membranewith at least one delivery port, which encapsulates the core. Thesemipermeable membrane controls the influx of water to the core from anaqueous environment of use so as to cause drug release by extrusionthrough the delivery port(s).

In addition to the active ingredient(s), the core of the osmotic deviceoptionally includes an osmotic agent, which creates a driving force fortransport of water from the environment of use into the core of thedevice. One class of osmotic agents is water-swellable hydrophilicpolymers, which are also referred to as “osmopolymers” and “hydrogels.”Suitable water-swellable hydrophilic polymers as osmotic agents include,but are not limited to, hydrophilic vinyl and acrylic polymers,polysaccharides such as calcium alginate, polyethylene oxide (PEO),polyethylene glycol (PEG), polypropylene glycol (PPG),poly(2-hydroxyethyl methacrylate), poly(acrylic) acid, poly(methacrylic)acid, polyvinylpyrrolidone (PVP), crosslinked PVP, polyvinyl alcohol(PVA), PVA/PVP copolymers, PVA/PVP copolymers with hydrophobic monomerssuch as methyl methacrylate and vinyl acetate, hydrophilic polyurethanescontaining large PEO blocks, sodium croscarmellose, carrageenan,hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC),hydroxypropyl methyl cellulose (HPMC), carboxymethyl cellulose (CMC) andcarboxyethyl, cellulose (CEC), sodium alginate, polycarbophil, gelatin,xanthan gum, and sodium starch glycolate.

The other class of osmotic agents is osmogens, which are capable ofimbibing water to affect an osmotic pressure gradient across the barrierof the surrounding coating. Suitable osmogens include, but are notlimited to, inorganic salts, such as magnesium sulfate, magnesiumchloride, calcium chloride, sodium chloride, lithium chloride, potassiumsulfate, potassium phosphates, sodium carbonate, sodium sulfite, lithiumsulfate, potassium chloride, and sodium sulfate; sugars, such asdextrose, fructose, glucose, inositol, lactose, maltose, mannitol,raffinose, sorbitol, sucrose, trehalose, and xylitol; organic acids,such as ascorbic acid, benzoic acid, fumaric acid, citric acid, maleicacid, sebacic acid, sorbic acid, adipic acid, edetic acid, glutamicacid, p-toluenesulfonic acid, succinic acid, and tartaric acid; urea;and mixtures thereof.

Osmotic agents of different dissolution rates can be employed toinfluence how rapidly the active ingredient(s) is initially deliveredfrom the dosage form. For example, amorphous sugars, such as MANNOGEM™EZ (SPI Pharma, Lewes, DE) can be used to provide faster delivery duringthe first couple of hours to promptly produce the desired therapeuticeffect, and gradually and continually release of the remaining amount tomaintain the desired level of therapeutic or prophylactic effect over anextended period of time. In this case, the active ingredient(s) isreleased at such a rate to replace the amount of the active ingredientmetabolized and excreted.

The core can also include a wide variety of other excipients andcarriers as described herein to enhance the performance of the dosageform or to promote stability or processing.

Materials useful in forming the semipermeable membrane include variousgrades of acrylics, vinyls, ethers, polyamides, polyesters, andcellulosic derivatives that are water-permeable and water-insoluble atphysiologically relevant pHs, or are susceptible to being renderedwater-insoluble by chemical alteration, such as crosslinking. Examplesof suitable polymers useful in forming the coating, include plasticized,unplasticized, and reinforced cellulose acetate (CA), cellulosediacetate, cellulose triacetate, CA propionate, cellulose nitrate,cellulose acetate butyrate (CAB), CA ethyl carbamate, CAP, CA methylcarbamate, CA succinate, cellulose acetate trimellitate (CAT), CAdimethylaminoacetate, CA ethyl carbonate, CA chloroacetate, CA ethyloxalate, CA methyl sulfonate, CA butyl sulfonate, CA p-toluenesulfonate, agar acetate, amylose triacetate, beta glucan acetate, betaglucan triacetate, acetaldehyde dimethyl acetate, triacetate of locustbean gum, hydroxylated ethylene-vinylacetate, EC, PEG, PPG, PEG/PPGcopolymers, PVP, HEC, HPC, CMC, CMEC, HPMC, HPMCP, HPMCAS, HPMCAT,poly(acrylic) acids and esters and poly-(methacrylic) acids and estersand copolymers thereof, starch, dextran, dextrin, chitosan, collagen,gelatin, polyalkenes, polyethers, polysulfones, polyethersulfones,polystyrenes, polyvinyl halides, polyvinyl esters and ethers, naturalwaxes, and synthetic waxes.

Semipermeable membrane can also be a hydrophobic microporous membrane,wherein the pores are substantially filled with a gas and are not wettedby the aqueous medium but are permeable to water vapor, as disclosed inU.S. Pat. No. 5,798,119. Such hydrophobic but water-vapor permeablemembrane are typically composed of hydrophobic polymers such aspolyalkenes, polyethylene, polypropylene, polytetrafluoroethylene,polyacrylic acid derivatives, polyethers, polysulfones,polyethersulfones, polystyrenes, polyvinyl halides, polyvinylidenefluoride, polyvinyl esters and ethers, natural waxes, and syntheticwaxes.

The delivery port(s) on the semipermeable membrane can be formedpost-coating by mechanical or laser drilling. Delivery port(s) can alsobe formed in situ by erosion of a plug of water-soluble material or byrupture of a thinner portion of the membrane over an indentation in thecore. In addition, delivery ports can be formed during coating process,as in the case of asymmetric membrane coatings of the type disclosed inU.S. Pat. Nos. 5,612,059 and 5,698,220.

The total amount of the active ingredient(s) released and the releaserate can substantially by modulated via the thickness and porosity ofthe semipermeable membrane, the composition of the core, and the number,size, and position of the delivery ports.

The pharmaceutical compositions in an osmotic controlled-release dosageform can further comprise additional conventional excipients or carriersas described herein to promote performance or processing of theformulation.

The osmotic controlled-release dosage forms can be prepared according toconventional methods and techniques known to those skilled in the art.See, Remington: The Science and Practice of Pharmacy, supra; Santus andBaker, J. Controlled Release 1995, 35, 1-21; Verma et al., DrugDevelopment and Industrial Pharmacy 2000, 26, 695-708; and Verma et al.,J. Controlled Release 2002, 79, 7-27.

In certain embodiments, the pharmaceutical compositions provided hereinare formulated as AMT controlled-release dosage form, which comprises anasymmetric osmotic membrane that coats a core comprising the activeingredient(s) and other pharmaceutically acceptable excipients orcarriers. See, U.S. Pat. No. 5,612,059 and International Publ. No. WO2002/17918. The AMT controlled-release dosage forms can be preparedaccording to conventional methods and techniques known to those skilledin the art, including direct compression, dry granulation, wetgranulation, and a dip-coating method.

In certain embodiments, the pharmaceutical compositions provided hereinare formulated as ESC controlled-release dosage form, which comprises anosmotic membrane that coats a core comprising the active ingredient(s),a hydroxylethyl cellulose, and other pharmaceutically acceptableexcipients or carriers.

3. Multiparticulate Controlled Release Devices

The pharmaceutical compositions provided herein in a modified releasedosage form can be fabricated as a multiparticulate controlled releasedevice, which comprises a multiplicity of particles, granules, orpellets, ranging from about 10 μm to about 3 mm, about 50 μm to about2.5 mm, or from about 100 μm to about 1 mm in diameter. Suchmultiparticulates can be made by the processes known to those skilled inthe art, including wet- and dry-granulation, extrusion/spheronization,roller-compaction, melt-congealing, and by spray-coating seed cores.See, for example, Multiparticulate Oral Drug Delivery; Ghebre-SellassieEd.; Marcel Dekker: 1994; and Pharmaceutical Pelletization Technology;Ghebre-Sellassie Ed.; Marcel Dekker: 1989.

Other excipients or carriers as described herein can be blended with thepharmaceutical compositions to aid in processing and forming themultiparticulates. The resulting particles can themselves constitute themultiparticulate device or can be coated by various film-formingmaterials, such as enteric polymers, water-swellable, and water-solublepolymers. The multiparticulates can be further processed as a capsule ora tablet.

4. Targeted Delivery

The pharmaceutical compositions provided herein can also be formulatedto be targeted to a particular tissue, receptor, or other area of thebody of the subject to be treated, including liposome-, resealederythrocyte-, and antibody-based delivery systems. Examples include, butare not limited to, those disclosed in U.S. Pat. Nos. 5,709,874;5,759,542; 5,840,674; 5,900,252; 5,972,366; 5,985,307; 6,004,534;6,039,975; 6,048,736; 6,060,082; 6,071,495; 6,120,751; 6,131,570;6,139,865; 6,253,872; 6,271,359; 6,274,552; 6,316,652; and 7,169,410.

Methods of Use

In one embodiment, provided herein is a method of treating, preventing,or ameliorating one or more symptoms of a RC kinase-mediated disorder,disease, or condition in a subject, comprising administering to thesubject a compound provided herein, e.g., a compound of Formula I,including a stereoisomer, enantiomer, mixture of enantiomers, mixture ofdiastereomers, or isotopic variant thereof; or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof

In another embodiments, provided herein is a method of treating,preventing, or ameliorating one or more symptoms of a disorder, disease,or condition responsive to the modulation of RC kinase activity in asubject, administering to the subject a compound provided herein, e.g.,a compound of Formula I, including a stereoisomer, enantiomer, mixtureof enantiomers, mixture of diastereomers, or isotopic variant thereof;or a pharmaceutically acceptable salt, solvate, hydrate, or prodrugthereof.

In yet another embodiments, provided herein is a method of treating,preventing, or ameliorating one or more symptoms of a disorder, disease,or condition responsive to the inhibition of RC kinase activity in asubject, administering to the subject a compound provided herein, e.g.,a compound of Formula I, including a stereoisomer, enantiomer, mixtureof enantiomers, mixture of diastereomers, or isotopic variant thereof;or a pharmaceutically acceptable salt, solvate, hydrate, or prodrugthereof.

In yet another embodiment, provided herein is a method for treating,preventing, or ameliorating one or more symptoms of aneosinophil-related disorder, disease, or condition in a subject,comprising administering to the subject a compound provided herein,e.g., a compound of Formula I, including a stereoisomer, enantiomer,mixture of enantiomers, mixture of diastereomers, or isotopic variantthereof; or a pharmaceutically acceptable salt, solvate, hydrate, orprodrug thereof

In yet another embodiment, provided herein is a method for treating,preventing, or ameliorating one or more symptoms of a basophil-relateddisorder, disease, or condition in a subject, comprising administeringto the subject a compound provided herein, e.g., a compound of FormulaI, including a stereoisomer, enantiomer, mixture of enantiomers, mixtureof diastereomers, or isotopic variant thereof; or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof

In yet another embodiment, provided herein is a method for treating,preventing, or ameliorating one or more symptoms of a mast cell-relateddisorder, disease, or condition in a subject, comprising administeringto the subject a compound provided herein, e.g., a compound of FormulaI, including a stereoisomer, enantiomer, mixture of enantiomers, mixtureof diastereomers, or isotopic variant thereof; or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof

In still another embodiment, provided herein is a method for treating,preventing, or ameliorating one or more symptoms of an inflammatorydisease in a subject, comprising administering to the subject a compoundprovided herein, e.g., a compound of Formula I, including astereoisomer, enantiomer, mixture of enantiomers, mixture ofdiastereomers, or isotopic variant thereof; or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof.

In one embodiment, the subject is a mammal. In another embodiment, thesubject is a human.

The disorders, diseases, or conditions treatable with a compoundprovided herein, e.g., a compound of Formula I, including astereoisomer, enantiomer, mixture of enantiomers, mixture ofdiastereomers, or isotopic variant thereof; or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof; include, but arenot limited to, (1) inflammatory or allergic diseases, includingsystemic anaphylaxis and hypersensitivity disorders, atopic dermatitis,urticaria, drug allergies, insect sting allergies, food allergies(including celiac disease and the like), and mastocytosis; (2)inflammatory bowel diseases, including Crohn's disease, ulcerativecolitis, ileitis, and enteritis; (3) vasculitis, and Behcet's syndrome;(4) psoriasis and inflammatory dermatoses, including dermatitis, eczema,atopic dermatitis, allergic contact dermatitis, urticaria, viralcutaneous pathologies including those derived from human papillomavirus,HIV or RLV infection, bacterial, flugal, and other parasital cutaneouspathologies, and cutaneous lupus erythematosus; (5) asthma andrespiratory allergic diseases, including allergic asthma, exerciseinduced asthma, allergic rhinitis, otitis media, allergicconjunctivitis, hypersensitivity lung diseases, and chronic obstructivepulmonary disease; (6) autoimmune diseases, including arthritis(including rheumatoid and psoriatic), systemic lupus erythematosus, typeI diabetes, myasthenia gravis, multiple sclerosis, Graves' disease, andglomerulonephritis; (7) graft rejection (including allograft rejectionand graft-v-host disease), e.g., skin graft rejection, solid organtransplant rejection, bone marrow transplant rejection; (8) fever; (9)cardiovascular disorders, including acute heart failure, hypotension,hypertension, angina pectoris, myocardial infarction, cardiomyopathy,congestive heart failure, atherosclerosis, coronary artery disease,restenosis, and vascular stenosis; (10) cerebrovascular disorders,including traumatic brain injury, stroke, ischemic reperfusion injuryand aneurysm; (11) cancers of the breast, skin, prostate, cervix,uterus, ovary, testes, bladder, lung, liver, larynx, oral cavity, colonand gastrointestinal tract (e.g., esophagus, stomach, pancreas), brain,thyroid, blood, and lymphatic system; (12) fibrosis, connective tissuedisease, and sarcoidosis, (13) genital and reproductive conditions,including erectile dysfunction; (14) gastrointestinal disorders,including gastritis, ulcers, nausea, pancreatitis, and vomiting; (15)neurologic disorders, including Alzheimer's disease; (16) sleepdisorders, including insomnia, narcolepsy, sleep apnea syndrome, andPickwick Syndrome; (17) pain; (18) renal disorders; (19) oculardisorders, including glaucoma; and (20) infectious diseases, includingHIV.

In certain embodiments, the disorder, disease, or condition is selectedfrom the group consisting of asthma, allergic asthma, exercise inducedasthma, allergic rhinitis, perennial allergic rhinitis, seasonalallergic rhinitis, atopic dermatitis, contact hypersensitivity, contactdermatitis, conjunctivitis, allergic conjunctivitis, eosinophilicbronchitis, food allergies, eosinophilic gastroenteritis, inflammatorybowel disease, ulcerative colitis, Crohn's disease, mastocytosis, hyperIgE syndrome, systemic lupus erythematous, psoriasis, acne, multiplesclerosis, allograft rejection, reperfusion injury, chronic obstructivepulmonary disease (COPD), Churg-Strauss syndrome, sinusitis, basophilicleukemia, chronic urticaria, basophilic leukocytosis, eczema, arthritis,rheumatoid arthritis, psoriatic arthritis, and osteoarthritis.

In certain embodiments, the disorder, disease, or condition is asthma,exercise induced asthma, allergic rhinitis, atopic dermatitis, chronicobstructive plumonary disease, or allergic conjunctivitis. In certainembodiments, the disorder, disease, or condition is COPD.

Depending on the disorder, disease, or condition to be treated, and thesubject's condition, the compounds or pharmaceutical compositionsprovided herein can be administered by oral, parenteral (e.g.,intramuscular, intraperitoneal, intravenous, ICV, intracistemalinjection or infusion, subcutaneous injection, or implant), inhalation,nasal, vaginal, rectal, sublingual, or topical (e.g., transdermal orlocal) routes of administration and can be formulated, alone ortogether, in suitable dosage unit with pharmaceutically acceptableexcipients, carriers, adjuvants, and vehicles appropriate for each routeof administration. Also provided herein is administration of thecompounds or pharmaceutical compositions provided herein in a depotformulation, in which the active ingredient is released over apredefined time period.

In the treatment, prevention, or amelioration of one or more symptoms ofthe disorders, diseases, and conditions, an appropriate dosage levelgenerally is ranging from about 0.001 to 100 mg per kg subject bodyweight per day (mg/kg per day), from about 0.01 to about 75 mg/kg perday, from about 0.1 to about 50 mg/kg per day, from about 0.5 to about25 mg/kg per day, or from about 1 to about 20 mg/kg per day, which canbe administered in single or multiple doses. Within this range, thedosage can be ranging from about 0.005 to about 0.05, from about 0.05 toabout 0.5, from about 0.5 to about 5.0, from about 1 to about 15, fromabout 1 to about 20, or from about 1 to about 50 mg/kg per day. Incertain embodiments, the dosage level is ranging from about 0.001 toabout 100 mg/kg per day. In certain embodiments, the dosage level isranging from about 0.01 to about 75 mg/kg per day. In certainembodiments, the dosage level is ranging from about 0.1 to about 50mg/kg per day. In certain embodiments, the dosage level is ranging fromabout 0.5 to about 25 mg/kg per day. In certain embodiments, the dosagelevel is ranging from about 1 to about 20 mg/kg per day.

For oral administration, the pharmaceutical compositions provided hereincan be formulated in the form of tablets containing from about 1.0 toabout 1,000 mg of the active ingredient, in one embodiment, about 1,about 5, about 10, about 15, about 20, about 25, about 50, about 75,about 100, about 150, about 200, about 250, about 300, about 400, about500, about 600, about 750, about 800, about 900, and about 1,000 mg ofthe active ingredient for the symptomatic adjustment of the dosage tothe patient to be treated. The pharmaceutical compositions can beadministered on a regimen of 1 to 4 times per day, including once,twice, three times, and four times per day.

It will be understood, however, that the specific dose level andfrequency of dosage for any particular patient can be varied and willdepend upon a variety of factors including the activity of the specificcompound employed, the metabolic stability and length of action of thatcompound, the age, body weight, general health, sex, diet, mode and timeof administration, rate of excretion, drug combination, the severity ofthe particular condition, and the host undergoing therapy.

In one embodiment, provided herein are methods of modulating RC kinaseactivity, comprising contacting a RC kinase with a compound providedherein, e.g., a compound of Formula I, including a stereoisomer,enantiomer, mixture of enantiomers, mixture of diastereomers, orisotopic variant thereof; or a pharmaceutically acceptable salt,solvate, hydrate, or prodrug thereof. In one embodiment, the RC kinaseis expressed by a cell.

The compounds provided herein, e.g., a compound of Formula I, includinga stereoisomer, enantiomer, mixture of enantiomers, mixture ofdiastereomers, or isotopic variant thereof; or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof; can also becombined or used in combination with other agents useful in thetreatment, prevention, or amelioration of one or more symptoms of thedisorders, diseases, or conditions for which the compounds providedherein are useful, including, but not limited to, asthma, COPD, allergicrhinitis, eczema, psoriasis, atopic dermatitis, fever, sepsis, systemiclupus erythematosus, diabetes, rheumatoid arthritis, multiple sclerosis,atherosclerosis, transplant rejection, inflammatory bowel disease,cancer, infectious diseases, and those pathologies noted herein.

In certain embodiments, the compounds provided herein can be combinedwith one or more steroidal drugs known in the art, including, but notlimited to, aldosterone, beclometasone, betamethasone,deoxycorticosterone acetate, fludrocortisone, hydrocortisone (cortisol),prednisolone, prednisone, methylprednisolone, dexamethasone, andtriamcinolone.

In certain embodiments, the compounds provided herein can be combinedwith one or more antibacterial agents known in the art, including, butnot limited to, amikacin, amoxicillin, ampicillin, arsphenamine,azithromycin, aztreonam, azlocillin, bacitracin, carbenicillin,cefaclor, cefadroxil, cefamandole, cefazolin, cephalexin, cefdinir,cefditorin, cefepime, cefixime, cefoperazone, cefotaxime, cefoxitin,cefpodoxime, cefprozil, ceftazidime, ceftibuten, ceftizoxime,ceftriaxone, cefuroxime, chloramphenicol, cilastin, ciprofloxacin,clarithromycin, clindamycin, cloxacillin, colistin, dalfopristin,demeclocycline, dicloxacillin, dirithromycin, doxycycline, erythromycin,enrofloxacin, ertepenem, ethambutol, flucloxacillin, fosfomycin,furazolidone, gatifloxacin, geldanamycin, gentamicin, herbimycin,imipenem, isoniazid, kanamycin, levofloxacin, linezolid, lomefloxacin,loracarbef, mafenide, moxifloxacin, meropenem, metronidazole,mezlocillin, minocycline, mupirocin, nafcillin, neomycin, netilmicin,nitrofurantoin, norfloxacin, ofloxacin, oxytetracycline, penicillin,piperacillin, platensimycin, polymyxin B, prontocil, pyrazinamide,quinupristine, rifampin, roxithromycin, spectinomycin, streptomycin,sulfacetamide, sulfamethizole, sulfamethoxazole, teicoplanin,telithromycin, tetracycline, ticarcillin, tobramycin, trimethoprim,troleandomycin, trovafloxacin, and vancomycin.

In certain embodiments, the compounds provided herein can be combinedwith one or more antifungal agents known in the art, including, but notlimited to, amorolfine, amphotericin B, anidulafungin, bifonazole,butenafine, butoconazole, caspofungin, ciclopirox, clotrimazole,econazole, fenticonazole, filipin, fluconazole, isoconazole,itraconazole, ketoconazole, micafungin, miconazole, naftifine,natamycin, nystatin, oxyconazole, ravuconazole, posaconazole, rimocidin,sertaconazole, sulconazole, terbinafine, terconazole, tioconazole, andvoriconazole.

In certain embodiments, the compounds provided herein can be combinedwith one or more anticoagulants known in the art, including, but notlimited to, acenocoumarol, argatroban, bivalirudin, lepirudin,fondaparinux, heparin, phenindione, warfarin, and ximelagatran.

In certain embodiments, the compounds provided herein can be combinedwith one or more thrombolytics known in the art, including, but notlimited to, anistreplase, reteplase, t-PA (alteplase activase),streptokinase, tenecteplase, and urokinase.

In certain embodiments, the compounds provided herein can be combinedwith one or more non-steroidal anti-inflammatory agents known in theart, including, but not limited to, aceclofenac, acemetacin, amoxiprin,aspirin, azapropazone, benorilate, bromfenac, carprofen, celecoxib,choline magnesium salicylate, diclofenac, diflunisal, etodolac,etoricoxib, faislamine, fenbufen, fenoprofen, flurbiprofen, ibuprofen,indometacin, ketoprofen, ketorolac, lornoxicam, loxoprofen, lumiracoxib,meclofenamic acid, mefenamic acid, meloxicam, metamizole, methylsalicylate, magnesium salicylate, nabumetone, naproxen, nimesulide,oxyphenbutazone, parecoxib, phenylbutazone, piroxicam, salicylsalicylate, sulindac, sulfinpyrazone, suprofen, tenoxicam, tiaprofenicacid, and tolmetin.

In certain embodiments, the compounds provided herein can be combinedwith one or more antiplatelet agents known in the art, including, butnot limited to, abciximab, cilostazol, clopidogrel, dipyridamole,ticlopidine, and tirofibin.

The compounds provided herein can also be administered in combinationwith other classes of compounds, including, but not limited to, (1)alpha-adrenergic agents; (2) antiarrhythmic agents; (3)anti-atherosclerotic agents, such as ACAT inhibitors; (4) antibiotics,such as anthracyclines, bleomycins, mitomycin, dactinomycin, andplicamycin; (5) anticancer agents and cytotoxic agents, e.g., alkylatingagents, such as nitrogen mustards, alkyl sulfonates, nitrosoureas,ethylenimines, and triazenes; (6) anticoagulants, such as acenocoumarol,argatroban, bivalirudin, lepirudin, fondaparinux, heparin, phenindione,warfarin, and ximelagatran; (7) anti-diabetic agents, such as biguanides(e.g., metformin), glucosidase inhibitors (e.g., acarbose), insulins,meglitinides (e.g., repaglinide), sulfonylureas (e.g., glimepiride,glyburide, and glipizide), thiozolidinediones (e.g., troglitazone,rosiglitazone, and pioglitazone), and PPAR-gamma agonists; (8)antifungal agents, such as amorolfine, amphotericin B, anidulafungin,bifonazole, butenafine, butoconazole, caspofungin, ciclopirox,clotrimazole, econazole, fenticonazole, filipin, fluconazole,isoconazole, itraconazole, ketoconazole, micafungin, miconazole,naftifine, natamycin, nystatin, oxyconazole, ravuconazole, posaconazole,rimocidin, sertaconazole, sulconazole, terbinafine, terconazole,tioconazole, and voriconazole; (9) antiinflammatories, e.g.,non-steroidal anti-inflammatory agents, such as aceclofenac, acemetacin,amoxiprin, aspirin, azapropazone, benorilate, bromfenac, carprofen,celecoxib, choline magnesium salicylate, diclofenac, diflunisal,etodolac, etoricoxib, faislamine, fenbufen, fenoprofen, flurbiprofen,ibuprofen, indometacin, ketoprofen, ketorolac, lornoxicam, loxoprofen,lumiracoxib, meclofenamic acid, mefenamic acid, meloxicam, metamizole,methyl salicylate, magnesium salicylate, nabumetone, naproxen,nimesulide, oxyphenbutazone, parecoxib, phenylbutazone, piroxicam,salicyl salicylate, sulindac, sulfinpyrazone, suprofen, tenoxicam,tiaprofenic acid, and tolmetin; (10) antimetabolites, such as folateantagonists, purine analogues, and pyrimidine analogues; (11)anti-platelet agents, such as GPIIb/IIIa blockers (e.g., abciximab,eptifibatide, and tirofiban), P2Y(AC) antagonists (e.g., clopidogrel,ticlopidine and CS-747), cilostazol, dipyridamole, and aspirin; (12)antiproliferatives, such as methotrexate, FK506 (tacrolimus), andmycophenolate mofetil; (13) anti-TNF antibodies or soluble TNF receptor,such as etanercept, rapamycin, and leflunimide; (14) aP2 inhibitors;(15) beta-adrenergic agents, such as carvedilol and metoprolol; (16)bile acid sequestrants, such as questran; (17) calcium channel blockers,such as amlodipine besylate; (18) chemotherapeutic agents; (19)cyclooxygenase-2 (COX-2) inhibitors, such as celecoxib and rofecoxib;(20) cyclosporins; (21) cytotoxic drugs, such as azathioprine andcyclophosphamide; (22) diuretics, such as chlorothiazide,hydrochlorothiazide, flumethiazide, hydroflumethiazide,bendroflumethiazide, methylchlorothiazide, trichloromethiazide,polythiazide, benzothiazide, ethacrynic acid, ticrynafen,chlorthalidone, furosenide, muzolimine, bumetanide, triamterene,amiloride, and spironolactone; (23) endothelin converting enzyme (ECE)inhibitors, such as phosphoramidon; (24) enzymes, such asL-asparaginase; (25) Factor VIIa Inhibitors and Factor Xa Inhibitors;(26) farnesyl-protein transferase inhibitors; (27) fibrates; (28) growthfactor inhibitors, such as modulators of PDGF activity; (29) growthhormone secretagogues; (30) HMG CoA reductase inhibitors, such aspravastatin, lovastatin, atorvastatin, simvastatin, NK-104 (a.k.a.itavastatin, nisvastatin, or nisbastatin), and ZD-4522 (also known asrosuvastatin, atavastatin, or visastatin); neutral endopeptidase (NEP)inhibitors; (31) hormonal agents, such as glucocorticoids (e.g.,cortisone), estrogens/antiestrogens, androgens/antiandrogens,progestins, and luteinizing hormone-releasing hormone antagonists, andoctreotide acetate; (32) immunosuppressants; (33) mineralocorticoidreceptor antagonists, such as spironolactone and eplerenone; (34)microtubule-disruptor agents, such as ecteinascidins; (35)microtubule-stabilizing agents, such as pacitaxel, docetaxel, andepothilones A-F; (36) MTP Inhibitors; (37) niacin; (38)phosphodiesterase inhibitors, such as PDE III inhibitors (e.g.,cilostazol) and PDE V inhibitors (e.g., sildenafil, tadalafil, andvardenafil); (39) plant-derived products, such as vinca alkaloids,epipodophyllotoxins, and taxanes; (40) platelet activating factor (PAF)antagonists; (41) platinum coordination complexes, such as cisplatin,satraplatin, and carboplatin; (42) potassium channel openers; (43)prenyl-protein transferase inhibitors; (44) protein tyrosine kinaseinhibitors; (45) renin inhibitors; (46) squalene synthetase inhibitors;(47) steroids, such as aldosterone, beclometasone, betamethasone,deoxycorticosterone acetate, fludrocortisone, hydrocortisone (cortisol),prednisolone, prednisone, methylprednisolone, dexamethasone, andtriamcinolone; (48) TNF-alpha inhibitors, such as tenidap; (49) thrombininhibitors, such as hirudin; (50) thrombolytic agents, such asanistreplase, reteplase, tenecteplase, tissue plasminogen activator(tPA), recombinant tPA, streptokinase, urokinase, prourokinase, andanisoylated plasminogen streptokinase activator complex (APSAC); (51)thromboxane receptor antagonists, such as ifetroban; (52) topoisomeraseinhibitors; (53) vasopeptidase inhibitors (dual NEP-ACE inhibitors),such as omapatrilat and gemopatrilat; and (54) other miscellaneousagents, such as, hydroxyurea, procarbazine, mitotane,hexamethylmelamine, and gold compounds.

Such other agents, or drugs, can be administered, by a route and in anamount commonly used therefor, simultaneously or sequentially with thecompounds provided herein, e.g., a compound of Formula I, including astereoisomer, enantiomer, mixture of enantiomers, mixture ofdiastereomers, or isotopic variant thereof; or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof. When a compoundprovided herein is used contemporaneously with one or more other drugs,a pharmaceutical composition containing such other drugs in addition tothe compound provided herein can be utilized, but is not required.Accordingly, the pharmaceutical compositions provided herein includethose that also contain one or more other active ingredients ortherapeutic agents, in addition to a compound provided herein.

The weight ratio of a compound provided herein to the second activeingredient can be varied, and will depend upon the effective dose ofeach ingredient. Generally, an effective dose of each will be used.Thus, for example, when a compound provided herein is combined with aNSAID, the weight ratio of the compound to the NSAID can range fromabout 1,000:1 to about 1:1,000, or about 200:1 to about 1:200.Combinations of a compound provided herein and other active ingredientswill generally also be within the aforementioned range, but in eachcase, an effective dose of each active ingredient should be used.

The compounds provided herein can also be provided as an article ofmanufacture using packaging materials well known to those of skill inthe art. See, e.g., U.S. Pat. Nos. 5,323,907; 5,052,558; and 5,033,252.Examples of pharmaceutical packaging materials include, but are notlimited to, blister packs, bottles, tubes, inhalers, pumps, bags, vials,containers, syringes, and any packaging material suitable for a selectedformulation and intended mode of administration and treatment.

Provided herein also are kits which, when used by the medicalpractitioner, can simplify the administration of appropriate amounts ofactive ingredients to a subject. In certain embodiments, the kitprovided herein includes a container and a dosage form of a compoundprovided herein, e.g., a compound of Formula I, including astereoisomer, enantiomer, mixture of enantiomers, mixture ofdiastereomers, or isotopic variant thereof; or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof.

In certain embodiments, the kit includes a container comprising a dosageform of the compound provided herein, e.g., a compound of Formula I,including a stereoisomer, enantiomer, mixture of enantiomers, mixture ofdiastereomers, or isotopic variant thereof; or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof, in a containercomprising one or more other therapeutic agent(s) described herein.

Kits provided herein can further include devices that are used toadminister the active ingredients. Examples of such devices include, butare not limited to, syringes, needle-less injectors drip bags, patches,and inhalers. The kits provided herein can also include condoms foradministration of the active ingredients.

Kits provided herein can further include pharmaceutically acceptablevehicles that can be used to administer one or more active ingredients.For example, if an active ingredient is provided in a solid form thatmust be reconstituted for parenteral administration, the kit cancomprise a sealed container of a suitable vehicle in which the activeingredient can be dissolved to form a particulate-free sterile solutionthat is suitable for parenteral administration. Examples ofpharmaceutically acceptable vehicles include, but are not limited to:aqueous vehicles, including, but not limited to, Water for InjectionUSP, Sodium Chloride Injection, Ringer's Injection, Dextrose Injection,Dextrose and Sodium Chloride Injection, and Lactated Ringer's Injection;water-miscible vehicles, including, but not limited to, ethyl alcohol,polyethylene glycol, and polypropylene glycol; and non-aqueous vehicles,including, but not limited to, corn oil, cottonseed oil, peanut oil,sesame oil, ethyl oleate, isopropyl myristate, and benzyl benzoate.

The disclosure will be further understood by the following non-limitingexamples.

EXAMPLES

As used herein, the symbols and conventions used in these processes,schemes and examples, regardless of whether a particular abbreviation isspecifically defined, are consistent with those used in the contemporaryscientific literature, for example, the Journal of the American ChemicalSociety or the Journal of Biological Chemistry. Specifically, butwithout limitation, the following abbreviations may be used in theexamples and throughout the specification: g (grams); mg (milligrams);mL (milliliters); μL (microliters); L (liter); mM (millimolar); μM(micromolar); Hz (Hertz); MHz (megahertz); mmol (millimoles); eq.(equivalent); hr or hrs (hours); min (minutes); MS (mass spectrometry);NMR (nuclear magnetic resonance); ESI (electrospray ionization); ACN(acetonitrile); CDCl₃ (deuterated chloroform); DCM (dichloromethane);DMF (N,N-dimethylformamide); DMSO (dimethylsulfoxide); DMSO-d₆(deuterated dimethylsulfoxide); EtOAc (ethyl acetate); EtOH (ethanol);Et₂O (diethylether); MeOH (methanol); PE (petroleum ether); TBDME(tert-butyldimethylether); THF (tetrahydrofuran); DIPEA(N,N-diisopropylethylamine); TEA (triethylamine); DBU(1,8-diazabicyclo[5.4.0]undec-7-ene); DMAP (4-dimethylaminopyridine);AIBN (1,1′-azobis(cyclohexanecarbonitrile); CDI (carbonyldiimidazole);EDCI or EDC (N′-ethyl-N-(3-dimethylaminopropyl)-carbodiimide); TBTU(O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate);Me (methyl); Et (ethyl); iPr (isopropyl); tBu (tert-butyl); Boc(tert-butoxylcarbonyl); Cbz (benzylcarbomate); Fmoc (9-fluorenylmethylcarbomate); Bn (benzyl); PMB (para-methoxy benzyl); Bs(4-bromo-benzenesulfonyl); TMS (trimethylsilyl); TsOH (tosylic acid);TsO (tosylate); DEAD (diethylazodicarboxylate), DIAD(diisopropylazodicarboxylate); AcCl (acetyl chloride); TFA(trifluoroacetic acid); TBAF (tetra-n-butylammonium fluoride); and tBuOK(potassium tert-butoxide).

For all of the following examples, standard work-up and purificationmethods known to those skilled in the art can be utilized. Unlessotherwise indicated, all temperatures are expressed in ° C. (degreesCentigrade). All reactions conducted at room temperature unlessotherwise noted. Synthetic methodologies herein are intended toexemplify the applicable chemistry through the use of specific examplesand are not indicative of the scope of the disclosure. Examples ofrelated syntheses may be found, e.g., in U.S. patent application Ser.Nos. 13/830,486 and 13/830,712, the disclosure of each of which isincorporated herein by reference in its entirety.

The starting materials used in the examples described herein are eithercommercially available or can be prepared by a method known to one ofskill in the art.

Example 15-((4-hydroxy-3,5-dimethylbenzyl)amino)-3-((4-(4-isopropylpiperazin-1-yl)phenyl)amino)-1H-pyrazole-4-carboxamide1

Compound 1 was prepared according to Scheme 1.

Preparation of 2-cyano-3,3-bis(methylthio)acrylamide 1-2. A mixture of2-cyanoacetamide (10 g, 118.9 mmol) and potassium hydroxide (6.661 g,118.9) in ACN (100 mL) was stirred at room temperature for 1 hr followedby slow addition of carbon disulfide (9.054 g, 118.9 mmol) at roomtemperature. After the solution was stirred for 3 hrs at roomtemperature, dimethylsulfate (19.5 g, 154.6 mmol) was added and thereaction mixture was stirred overnight at room temperature. Thevolatiles were then removed under vacuum, and the residual wasredissolved in EtOAc and washed sequentially with water and brine, driedover anhydrous MgSO₄, and concentrated in vacuo. The resulting solid wastriturated with EtOAc/hexanes, filtered, and dried to give compound I-2(9.4 g, 42% yield, 99.0% purity) as a yellow solid.

2-cyano-3,3-bis(methylthio)acrylamide 1-2 (0.500 g) was dissolved in 15mL EtOH and 4-(4-(2-propyl)-piperazin-1-yl)aniline (1.0 eq.) was added.The reaction was stirred at 75° C. until the starting amide was absentby HPLC. Once complete (18 hrs), reaction was brought to roomtemperature and filtered to obtain2-cyano-3-((4-(4-isopropylpiperazin-1-yl)phenyl)amino)-3-(methylthio)acrylamideA1 as a purple powder. The product was allowed to dry under vacuum for 1hr.

2-cyano-3-((4-(4-isopropylpiperazin-1-yl)phenyl)amino)-3-(methylthio)acrylamideA1

2-cyano-3-((4-(4-isopropylpiperazin-1-yl)phenyl)amino)-3-(methylthio)acrylamideA1 was then suspended in 10 mL EtOH and hydrazine hydrate (1.0 eq.) wasadded dropwise. The reaction was heated at 75° C. until A1 was absent(HPLC). Once the intermediate was absent (18 hrs), the reaction wasbrought to room temperature and filtered to obtain5-amino-3-((4-(4-isopropylpiperazin-1-yl)phenyl)amino)-1H-pyrazole-4-carboxamideA2 as a purple powder. The product was allowed to dry under vacuum for 1hr.

5-amino-3-((4-(4-isopropylpiperazin-1-yl)phenyl)amino)-1H-pyrazole-4-carboxamideA2

5-amino-3-((4-(4-isopropylpiperazin-1-yl)phenyl)amino)-1H-pyrazole-4-carboxamide(0.200 g) A2 was suspended in EtOH (4 mL) and piperidine (5 drops). Thereaction mixture was heated at 80° C. while stirring, and3,5-dimethyl-4-hydroxybenzaldehyde (0.122 g) was added. After 18 h, thereaction mixture was cooled to room temperature. The separated solidswas collected by suction filtration and rinsed with ethanol to give thecrude imine product A3, which was used without purification.

To a suspension of A3 (246 mg) in DMF (2 mL) and MeOH (4 mL) was slowlyadded sodium borohydride (39 mg) at room temperature. After the reactionmixture was stirred at room temperature for 1 hr, water was added andthe resulting solid was collected by suction filtration. The recoveredprecipitate was dissolved in DMSO, filtered through a cotton plug, whichwas further rinsed with EtOH. The DMSO and EtOH filtrates were combined,and water was added until a precipitate formed. The resulting suspensionwas chilled in a refrigerator for 3 hours. The resulting precipitate wasfiltered, washed with water, and dried to yield compound 1 (75 mg, 95.1%purity) as a powder. ¹H-NMR (500 MHz, DMSO): 11.36 (s, 1H), 8.22 (s,1H), 8.13 (s, 1H), 7.12 (s, 2H), 6.91 (s, 2H), 6.79 (d, J=8 Hz, 2H),6.12 (s, 3H), 4.16 (d, J=8 Hz, 2H), 2.97 (m, 4H), 2.67 (m, 1H), 2.55 (m,4H), 2.18 (s, 6H), 1.00 (s, 6H).

Example 2 Synthesis of3-((3-chloro-4-morpholinophenyl)amino)-5-((4-hydroxy-3,5-dimethylbenzyl)amino)-1H-pyrazole-4-carboxamide2

The intermediate5-amino-3-((3-chloro-4-morpholinophenyl)amino)-1H-pyrazole-4-carboxamidewas prepared in a manner substantially similar to that described for A2of Example 1.

5-amino-3-((3-chloro-4-morpholinophenyl)amino)-1H-pyrazole-4-carboxamide(530 mg, 1.57 mmol) and 3,5-dimethyl-4-hydroxybenzaldehyde (0.285 g,1.90 mmol, 1.2 eq.) were suspended in EtOH (9 mL) and piperidine (5drops) was added. The reaction mixture was heated at 80° C. for 18 h andthen cooled to room temperature. The separated precipitate was collectedby suction filtration and rinsed with ethanol to give the crude imine asyellow powder.

To a suspension of imine (312 mg, 0.67 mmol) in DMF (15 mL) and MeOH (3mL) was slowly added sodium borohydride (51 mg, 1.34 mmol, 2.0 eq.) atroom temperature. After the reaction mixture was stirred at roomtemperature for 30 minutes, water (100 mL) was added until a clearsolution was obtained. To the resulting stirring solution, HCl (3.0 N)was added dropwise until the precipitate persisted. Stirring wascontinued on an ice bath for 1 h. The resulting precipitate wasfiltered, washed with water, and dried to yield compound 2 (291 mg. 93%yield, 95.7% purity) as a white powder. ¹H-NMR (500 MHz, DMSO): 11.47(s, 1H), 8.54 (s, 1H), 7.51 (s, 1H), 7.04 (s, 2H), 6.92 (s, 2H), 6.68(m, 3H), 4.17 (m, 2H), 3.71 (m, 4H), 2.86 (m, 4H), 2.14 (s, 6H).

Example 3 Synthesis of5-((4-hydroxy-3,5-dimethylbenzyl)amino)-3-((4-morpholinophenyl)amino)-1H-pyrazole-4-carboxamide3

The intermediate5-amino-3-((4-morpholinophenyl)amino)-1H-pyrazole-4-carboxamide wasprepared in a manner substantially similar to that described for A2 ofExample 1.

5-amino-3-((4-morpholinophenyl)amino)-1H-pyrazole-4-carboxamide (1.06 g,3.51 mmol) and 3,5-dimethyl-4-hydroxybenzaldehyde (0.790 g, 5.26 mmol,1.5 eq.) were suspended in EtOH (25 mL) and acetic acid (2.5 mL). Thereaction mixture was heated at 80° C. for 24 h and then cooled to roomtemperature and concentrated in vacuo to approximately half of theoriginal volume. The separated precipitate was collected by suctionfiltration and rinsed with ethanol to give the crude imine as an orangepowder.

To a solution of imine (1.36 g, 3.13 mmol) in DMSO (15 mL) and MeOH (3mL) was slowly added sodium borohydride (180 mg, 6.26 mmol, 2.0 eq.) atroom temperature. After the reaction mixture was stirred at roomtemperature for 48 hours, water was added and the resulting precipitatewas isolated by suction filtration and washed with water. The recoveredprecipitate was dissolved in DMSO (6 mL), filtered through a cottonplug, which was further rinsed with EtOH (3 mL). The DMSO and EtOHfiltrates were combined, and water was added until a precipitate formed.The resulting suspension was chilled in a refrigerator for 3 hours. Theresulting precipitate was filtered, washed with water, and dried toyield compound 3 (1.125 g. 82% yield, 97% purity) as a white powder.¹H-NMR (500 MHz, DMSO): 11.37 (s, 1H), 8.26 (s, 1H), 8.13 (s, 1H), 7.14(m, 2H), 6.92 (s, 2H), 6.81 (d, J=8 Hz, 2H), 6.63 (s, 2H), 4.16 (d, J=8Hz, 2H), 3.71 (m, 4H), 2.96 (m, 4H), 2.14 (s, 6H).

Example 4 Synthesis of3-((4-(2,6-dimethylmorpholino)phenyl)amino)-5-((4-hydroxy-3,5-dimethylbenzyl)amino)-1H-pyrazole-4-carboxamide4

The intermediate5-amino-3-((4-(2,6-dimethylmorpholino)phenyl)amino)-1H-pyrazole-4-carboxamidewas prepared in a manner substantially similar to that described for A2of Example 1.

5-amino-3-((4-(2,6-dimethylmorpholino)phenyl)amino)-1H-pyrazole-4-carboxamide(0.530 g) was suspended in EtOH (11 mL) and piperidine (5 drops). Thereaction mixture was heated at 80° C. while stirring, and3,5-dimethyl-4-hydroxybenzaldehyde (0.330 g) was added. After 18 h, thereaction mixture was cooled to room temperature. The separated solidswas collected by suction filtration and rinsed with ethanol to give thecrude imine product which was used without purification.

To a suspension of imine (100 mg) in DMF (1 mL) and MeOH (2 mL) wasslowly added sodium borohydride (17 mg) at room temperature. After thereaction mixture was stirred at room temperature for 1 hr, water wasadded and the resulting solid was collected by suction filtration. Therecovered precipitate was dissolved in DMSO, filtered through a cottonplug, which was further rinsed with EtOH. The DMSO and EtOH filtrateswere combined, and water was added until a precipitate formed. Theresulting suspension was chilled in a refrigerator for 3 hours. Theresulting precipitate was filtered, washed with water, and dried toyield compound 4 (60 mg, 99% purity) as a powder. ¹H-NMR (500 MHz,DMSO): 11.37 (s, 1H), 8.26 (s, 1H), 8.12 (s, 1H), 7.14 (m, 2H), 6.92 (s,2h), 6.81 (m, 2H), 6.62 (s, 3H), 4.16 (d, J=8 Hz, 2H), 3.68 (m, 2H),3.37 (d, J=8 Hz, 2H), 2.16 (s, 6H), 1.13 (d, J=8 Hz, 6H).

Example 5 Synthesis of3-((5-chloro-6-morpholinopyridin-3-yl)amino)-5-((4-hydroxy-3,5-dimethylbenzyl)amino)-1H-pyrazole-4-carboxamide5

The intermediate5-amino-3-((5-chloro-6-morpholinopyridin-3-yl)amino)-1H-pyrazole-4-carboxamidewas prepared in a manner substantially similar to that described for A2of Example 1.

5-amino-3-((5-chloro-6-morpholinopyridin-3-yl)amino)-1H-pyrazole-4-carboxamide(0.091 g) was suspended in EtOH (10 mL) and piperidine (5 drops). Thereaction mixture was heated at 80° C. while stirring, and3,5-dimethyl-4-hydroxybenzaldehyde (0.060 g) was added. After 18 h, thereaction mixture was cooled to room temperature. The separated solidswas collected by suction filtration and rinsed with ethanol to give thecrude imine product (122 mg) which was used without purification.

To a suspension of imine (122 mg) in DMF (3 mL) and MeOH (1 mL) wasslowly added sodium borohydride (20 mg) at room temperature. After thereaction mixture was stirred at room temperature for 1 hr, water wasadded and the resulting solid was collected by suction filtration. Therecovered precipitate was dissolved in DMSO, filtered through a cottonplug, which was further rinsed with EtOH. The DMSO and EtOH filtrateswere combined, and water was added until a precipitate formed. Theresulting suspension was chilled in a refrigerator for 3 hours. Theresulting precipitate was filtered, washed with water, and dried toyield compound 5 (99 mg, 96.5% purity) as a powder. ¹H-NMR (500 MHz,DMSO): 11.51 (s, 1H), 8.74 (s, 1H), 8.19 (s, 1H), 8.13 (s, 1H), 8.08 (s,1H), 6.92 (s, 2H), 6.74 (m, 3H), 4.17 (d, J=8 Hz, 2H), 3.72 (m, 4H),3.07 (m, 4H), 2.14 (s, 6H).

Example 6 Synthesis of3-((4-(1H-pyrrol-1-yl)phenyl)amino)-5-((4-hydroxy-3,5-dimethylbenzyl)amino)-1H-pyrazole-4-carboxamide6

The intermediate3-((4-(1H-pyrrol-1-yl)phenyl)amino)-5-amino-1H-pyrazole-4-carboxamidewas prepared in a manner substantially similar to that described for A2of Example 1.

3-((4-(1H-pyrrol-1-yl)phenyl)amino)-5-amino-1H-pyrazole-4-carboxamide(0.150 g) was suspended in EtOH (10 mL) and piperidine (5 drops). Thereaction mixture was heated at 80° C. while stirring, and3,5-dimethyl-4-hydroxybenzaldehyde (0.040 g) was added. After 18 h, thereaction mixture was cooled to room temperature. The separated solidswas collected by suction filtration and rinsed with ethanol to give thecrude imine product which was used without purification.

To a suspension of imine (275 mg) in DMF (2 mL) and MeOH (4 mL) wasslowly added sodium borohydride (50 mg) at room temperature. After thereaction mixture was stirred at room temperature for 1 hr, water wasadded and the resulting solid was collected by suction filtration. Therecovered precipitate was dissolved in DMSO, filtered through a cottonplug, which was further rinsed with EtOH. The DMSO and EtOH filtrateswere combined, and water was added until a precipitate formed. Theresulting suspension was chilled in a refrigerator for 3 hours. Theresulting precipitate was filtered, washed with water, and dried toyield compound 6 (75 mg, 99% purity) as a powder. ¹H-NMR (500 MHz,DMSO): 11.50 (s, 1H), 8.65 (s, 1H), 8.14 (s, 1H), 7.35 (m, 4H), 7.19 (s,2H), 6.93 (s, 2H), 6.68 (s, 3H), 6.20 (s, 2H), 4.18 (d, J=8 Hz, 2H),2.15 (s, 6H).

Example 7 Synthesis of5-((4-hydroxy-3,5-dimethylbenzyl)amino)-3-((6-morpholinopyridin-3-yl)amino)-1H-pyrazole-4-carboxamide7

The intermediate5-amino-3-((6-morpholinopyridin-3-yl)amino)-1H-pyrazole-4-carboxamidewas prepared in a manner substantially similar to that described for A2of Example 1.

5-amino-3-((6-morpholinopyridin-3-yl)amino)-1H-pyrazole-4-carboxamide(0.200 g) was suspended in EtOH (10 mL) and piperidine (5 drops). Thereaction mixture was heated at 80° C. while stirring, and3,5-dimethyl-4-hydroxybenzaldehyde (0.050 g) was added. After 18 h, thereaction mixture was cooled to room temperature. The separated solidswas collected by suction filtration and rinsed with ethanol to give thecrude imine product which was used without purification.

To a suspension of imine (241 mg) in DMF (2 mL) and MeOH (4 mL) wasslowly added sodium borohydride (42 mg) at room temperature. After thereaction mixture was stirred at room temperature for 1 hr, water wasadded and the resulting solid was collected by suction filtration. Therecovered precipitate was dissolved in DMSO, filtered through a cottonplug, which was further rinsed with EtOH. The DMSO and EtOH filtrateswere combined, and water was added until a precipitate formed. Theresulting suspension was chilled in a refrigerator for 3 hours. Theresulting precipitate was filtered, washed with water, and dried toyield compound 7 (75 mg, 99% purity) as a powder. ¹H-NMR (500 MHz,DMSO): 11.36 (s, 1H), 8.27 (s, 1H), 8.18 (s, 1H), 8.13 (s, 1H), 7.63 (s,1H), 6.91 (s, 2H), 6.74 (d, J=8 Hz, 1H), 6.66 (s, 3H), 4.16 (d, J=8 Hz,2H), 3.69 (m, 4H), 3.28 (m, 4H), 2.14 (s, 6H).

Example 8 Synthesis of5-((4-hydroxy-3,5-dimethylbenzyl)amino)-3-((3-methyl-4-morpholinophenyl)amino)-1H-pyrazole-4-carboxamide8

The intermediate5-amino-3-((3-methyl-4-morpholinophenyl)amino)-1H-pyrazole-4-carboxamidewas prepared in a manner substantially similar to that described for A2of Example 1.

5-amino-3-((3-methyl-4-morpholinophenyl)amino)-1H-pyrazole-4-carboxamide(0.150 g) was suspended in EtOH (3 mL) and piperidine (5 drops). Thereaction mixture was heated at 80° C. while stirring, and3,5-dimethyl-4-hydroxybenzaldehyde (0.100 g) was added. After 18 h, thereaction mixture was cooled to room temperature. The separated solidswas collected by suction filtration and rinsed with ethanol to give thecrude imine product which was used without purification.

To a suspension of imine (145 mg) in DMF (2 mL) and MeOH (4 mL) wasslowly added sodium borohydride (24 mg) at room temperature. After thereaction mixture was stirred at room temperature for 1 hr, water wasadded and the resulting solid was collected by suction filtration. Therecovered precipitate was dissolved in DMSO, filtered through a cottonplug, which was further rinsed with EtOH. The DMSO and EtOH filtrateswere combined, and water was added until a precipitate formed. Theresulting suspension was chilled in a refrigerator for 3 hours. Theresulting precipitate was filtered, washed with water, and dried toyield compound 8 (100 mg, 99% purity) as a powder. ¹H-NMR (500 MHz,DMSO): 11.43 (s, 1H), 8.34 (s, 1H), 8.13 (s, 1H), 7.07 (m, 2H), 6.91 (m,3H), 6.64 (s, 3H), 4.16 (d, J=8 Hz, 2H), 3.70 (m, 4H), 2.74 (m, 4H),2.19 (s, 3H), 2.15 (s, 6H).

Example 9 Synthesis of5-((4-hydroxy-3,5-dimethylbenzyl)amino)-3-((4-(pyridin-2-yl)phenyl)amino)-1H-pyrazole-4-carboxamide9

The intermediate5-amino-3-((4-(pyridin-2-yl)phenyl)amino)-1H-pyrazole-4-carboxamide wasprepared in a manner substantially similar to that described for A2 ofExample 1.

5-amino-3-((4-(pyridin-2-yl)phenyl)amino)-1H-pyrazole-4-carboxamide(0.200 g) was suspended in EtOH (4 mL) and piperidine (5 drops). Thereaction mixture was heated at 80° C. while stirring, and3,5-dimethyl-4-hydroxybenzaldehyde (0.143 g) was added. After 18 h, thereaction mixture was cooled to room temperature. The separated solidswas collected by suction filtration and rinsed with ethanol to give thecrude imine product which was used without purification.

To a suspension of imine (350 mg) in DMF (3 mL) and MeOH (6 mL) wasslowly added sodium borohydride (62 mg) at room temperature. After thereaction mixture was stirred at room temperature for 1 hr, water wasadded and the resulting solid was collected by suction filtration. Therecovered precipitate was dissolved in DMSO, filtered through a cottonplug, which was further rinsed with EtOH. The DMSO and EtOH filtrateswere combined, and water was added until a precipitate formed. Theresulting suspension was chilled in a refrigerator for 3 hours. Theresulting precipitate was filtered, washed with water, and dried toyield compound 9 (110 mg, 97.7% purity) as a powder. ¹H-NMR (500 MHz,DMSO): 11.58 (s, 1H), 8.85 (s, 1H), 8.57 (m, 1H), 8.15 (s, 1H), 7.95 (d,J=8 Hz, 2H), 7.79 (m, 4H), 7.33 (m, 2H), 7.21, (m, 1H), 6.94 (s, 2H),6.70 (s, 3H), 4.19 (m, 2H), 2.15 (s, 6H).

Example 10 Synthesis of5-((4-hydroxy-3,5-dimethylbenzyl)amino)-3-((4-(4-methylpiperazin-1-yl)phenyl)amino)-1H-pyrazole-4-carboxamide10

The intermediate5-amino-3-((4-(4-methylpiperazin-1-yl)phenyl)amino)-1H-pyrazole-4-carboxamidewas prepared in a manner substantially similar to that described for A2of Example 1.

5-amino-3-((4-(4-methylpiperazin-1-yl)phenyl)amino)-1H-pyrazole-4-carboxamide(0.250 g) was suspended in EtOH (5 mL) and piperidine (5 drops). Thereaction mixture was heated at 80° C. while stirring, and3,5-dimethyl-4-hydroxybenzaldehyde (0.167 g) was added. After 18 h, thereaction mixture was cooled to room temperature. The separated solidswas collected by suction filtration and rinsed with ethanol to give thecrude imine product which was used without purification.

To a suspension of imine (250 mg) in DMF (2 mL) and MeOH (4 mL) wasslowly added sodium borohydride (42 mg) at room temperature. After thereaction mixture was stirred at room temperature for 1 hr, water wasadded and the resulting solid was collected by suction filtration. Therecovered precipitate was dissolved in DMSO, filtered through a cottonplug, which was further rinsed with EtOH. The DMSO and EtOH filtrateswere combined, and water was added until a precipitate formed. Theresulting suspension was chilled in a refrigerator for 3 hours. Theresulting precipitate was filtered, washed with water, and dried toyield compound 10 (30 mg, 94% purity) as a powder. ¹H-NMR (500 MHz,DMSO): 11.38 (s, 1H), 8.29 (s, 1H), 8.13 (s, 1H), 7.15 (m, 2H), 6.92 (s,2H), 6.84 (m, 2H), 6.63 (s, 3H), 4.16 (s, 2H), 3.11 (s, 2H), 2.99 (s,2H), 2.89 (s, 2H), 2.58 (s, 3H), 2.14 (s, 6H), 1.57 (m, 2H), 1.23 (s,1H).

Example 11 Synthesis of5-((4-hydroxy-3,5-dimethylbenzyl)amino)-3-((5-morpholinopyridin-2-yl)amino)-1H-pyrazole-4-carboxamide11

The intermediate5-amino-3-((5-morpholinopyridin-2-yl)amino)-1H-pyrazole-4-carboxamidewas prepared in a manner substantially similar to that described for A2of Example 1.

5-amino-3-((5-morpholinopyridin-2-yl)amino)-1H-pyrazole-4-carboxamide(0.153 g) was suspended in EtOH (3 mL) and acetic acid (1 mL). Thereaction mixture was heated at 80° C. while stirring, and3,5-dimethyl-4-hydroxybenzaldehyde (0.105 g) was added. After 18 h, thereaction mixture was cooled to room temperature. The separated solidswas collected by suction filtration and rinsed with ethanol to give thecrude imine product which was used without purification.

To a suspension of imine (80 mg) in DMF (4 mL) and MeOH (2 mL) wasslowly added sodium borohydride (140 mg) at room temperature. After thereaction mixture was stirred at room temperature for 1 hr, water wasadded and the resulting solid was collected by suction filtration. Therecovered precipitate was dissolved in DMSO, filtered through a cottonplug, which was further rinsed with EtOH. The DMSO and EtOH filtrateswere combined, and water was added until a precipitate formed. Theresulting suspension was chilled in a refrigerator for 3 hours. Theresulting precipitate was filtered, washed with water, and dried toyield compound 11 (77 mg, 98.5% purity) as a powder. ¹H-NMR (500 MHz,DMSO): 11.93 (s, 0.4H), 11.43 (s, 0.6H), 9.65 (s, 0.4H), 9.15 (s, 0.6H),8.13 (s, 0.6H), 8.00 (s, 0.4H), 7.95 (s, 1H), 7.59 (d, 0.6H), 7.42 (m,0.4H), 7.32 (m, 0.6H), 6.94 (m, 2.3H), 6.77 (s, 0.8H), 6.70 (s, 1.2H),6.56 (m, 0.6H), 5.70 (m, 0.4H), 4.17 (m, 2H), 3.73 (s, 4H), 3.01 (m,4H), 2.14 (s, 6H).

Example 12 Synthesis of5-((4-hydroxy-3,5-dimethylbenzyl)amino)-3-((5-methyl-6-morpholinopyridin-3-yl)amino)-1H-pyrazole-4-carboxamide12

The intermediate5-amino-3-((5-methyl-6-morpholinopyridin-3-yl)amino)-1H-pyrazole-4-carboxamidewas prepared in a manner substantially similar to that described for A2of Example 1.

5-amino-3-((5-methyl-6-morpholinopyridin-3-yl)amino)-1H-pyrazole-4-carboxamide(0.340 g) was suspended in EtOH (18 mL) and acetic acid (1 mL). Thereaction mixture was heated at 80° C. while stirring, and3,5-dimethyl-4-hydroxybenzaldehyde (0.240 g) was added. After 18 h, thereaction mixture was cooled to room temperature. The separated solidswas collected by suction filtration and rinsed with ethanol to give thecrude imine product which was used without purification.

To a suspension of imine (73 mg) in DMF (2 mL) and MeOH (1 mL) wasslowly added sodium borohydride (12 mg) at room temperature. After thereaction mixture was stirred at room temperature for 1 hr, water wasadded and the resulting solid was collected by suction filtration. Therecovered precipitate was dissolved in DMSO, filtered through a cottonplug, which was further rinsed with EtOH. The DMSO and EtOH filtrateswere combined, and water was added until a precipitate formed. Theresulting suspension was chilled in a refrigerator for 3 hours. Theresulting precipitate was filtered, washed with water, and dried toyield compound 12 (60 mg, 97.6% purity) as a powder. ¹H-NMR (500 MHz,DMSO): 11.44 (s, 1H), 8.47 (s, 1H), 8.10 (s, 2H), 7.58 (s, 1H), 6.92 (s,2H), 6.68 (s, 3H), 4.16 (d, J=6 Hz, 2H), 3.71 (t, J=5 Hz, 4H), 2.91 (t,J=5 Hz, 4H), 2.20 (s, 3H), 2.14 (s, 6H).

Example 13 Synthesis of5-((4-hydroxy-3,5-dimethylbenzyl)amino)-3-((6-(4-isopropylpiperazin-1-yl)-5-methylpyridin-3-yl)amino)-1H-pyrazole-4-carboxamide13

The intermediate5-amino-3-((6-(4-isopropylpiperazin-1-yl)-5-methylpyridin-3-yl)amino)-1H-pyrazole-4-carboxamidewas prepared in a manner substantially similar to that described for A2of Example 1.

5-amino-3-((6-(4-isopropylpiperazin-1-yl)-5-methylpyridin-3-yl)amino)-1H-pyrazole-4-carboxamide(0.210 g) was suspended in EtOH (12 mL) and acetic acid (0.5 mL). Thereaction mixture was heated at 80° C. while stirring, and3,5-dimethyl-4-hydroxybenzaldehyde (0.130 g) was added. After 18 h, thereaction mixture was cooled to room temperature. The separated solidswas collected by suction filtration and rinsed with ethanol to give thecrude imine product which was used without purification.

To a suspension of imine (50 mg) in DMF (3 mL) and MeOH (1.5 mL) wasslowly added sodium borohydride (10 mg) at room temperature. After thereaction mixture was stirred at room temperature for 1 hr, water wasadded and the resulting solid was collected by suction filtration. Therecovered precipitate was dissolved in DMSO, filtered through a cottonplug, which was further rinsed with EtOH. The DMSO and EtOH filtrateswere combined, and water was added until a precipitate formed. Theresulting suspension was chilled in a refrigerator for 3 hours. Theresulting precipitate was filtered, washed with water, and dried toyield compound 13 (41 mg, 99.3% purity) as a powder. ¹H-NMR (500 MHz,DMSO): 11.43 (s, 1H), 8.43 (s, 1H), 8.14 (s, 1H), 8.07 (s, 1H), 7.55 (s,1H), 6.92 (s, 2H), 6.68 (s, 3H), 4.16 (d, J=6, 2H), 2.90 (m, 4H), 2.66(m, 1H) 2.56 (m, 4H), 2.18 (s, 3H), 2.14 (s, 6H), 1.00 (d, J=7, 6H).

Example 14 Synthesis of5-((4-hydroxy-3,5-dimethylbenzyl)amino)-3-((5-methyl-6-(4-methylpiperazin-1-yl)pyridin-3-yl)amino)-1H-pyrazole-4-carboxamide14

The intermediate5-amino-3-((5-methyl-6-(4-methylpiperazin-1-yl)pyridin-3-yl)amino)-1H-pyrazole-4-carboxamidewas prepared in a manner substantially similar to that described for A2of Example 1.

5-amino-3-((5-methyl-6-(4-methylpiperazin-1-yl)pyridin-3-yl)amino)-1H-pyrazole-4-carboxamide(0.21 g) was suspended in EtOH (8 mL) and acetic acid (1 mL). Thereaction mixture was heated at 80° C. while stirring, and3,5-dimethyl-4-hydroxybenzaldehyde (0.136 g) was added. After 16 h, thereaction mixture was cooled to room temperature. The separated solidswas collected by suction filtration and rinsed with ethanol to give thecrude imine product which was used without purification.

To a suspension of imine (153 mg) in DMF (3 mL) and MeOH (1 mL) wasslowly added sodium borohydride (25 mg) at room temperature. After thereaction mixture was stirred at room temperature for 1 hr, water wasadded and the resulting suspension was stirred for 30 min. The solid wascollected by suction filtration, washed with water, and dried to yieldcompound 14 (41 mg, 99.3% purity) as a white powder. ¹H-NMR (500 MHz,DMSO): 11.43 (s, 1H), 8.51 and 8.44 (s,s, 1H), 8.12 and 8.08 (s,s, 2H),7.59 and 7.56 (s,s, 1H), 6.92 (s, 2H), 6.69 (d, J=5 Hz, 3H), 4.16 (d,J=6 Hz, 2H), 3.17 (m, 1H), 3.04 (m, 1H), 2.91 (m, 4H), 2.60 (s, 1H),2.44 (s, 2H), 2.22 (s, 2H), 2.18 (d, J=3 Hz, 3H), 2.14 (s, 6H).

Example 15 Synthesis of3-((3-chloro-4-(2,6-dimethylmorpholino)phenyl)amino)-5-((4-hydroxy-3,5-dimethylbenzyl)amino)-1H-pyrazole-4-carboxamide15

The intermediate5-amino-3-((3-chloro-4-(2,6-dimethylmorpholino)phenyl)amino)-1H-pyrazole-4-carboxamidewas prepared in a manner substantially similar to that described for A2of Example 1.

5-amino-3-((3-chloro-4-(2,6-dimethylmorpholino)phenyl)amino)-1H-pyrazole-4-carboxamide(0.235 g) was suspended in EtOH (4.7 mL) and piperidine (5 drops). Thereaction mixture was heated at 80° C. while stirring, and3,5-dimethyl-4-hydroxybenzaldehyde (0.145 g) was added. After 18 h, thereaction mixture was cooled to room temperature. The separated solidswas collected by suction filtration and rinsed with ethanol to give thecrude imine product which was used without purification.

To a suspension of imine (55 mg) in DMF (1 mL) and MeOH (1 mL) wasslowly added sodium borohydride (8 mg) at room temperature. After thereaction mixture was stirred at room temperature for 1 hr, water wasadded and the resulting solid was collected by suction filtration. Therecovered precipitate was dissolved in DMSO, filtered through a cottonplug, which was further rinsed with EtOH. The DMSO and EtOH filtrateswere combined, and water was added until a precipitate formed. Theresulting suspension was chilled in a refrigerator for 3 hours. Theresulting precipitate was filtered, washed with water, and dried toyield compound 15 (55 mg, 97.5% purity) as a powder. ¹H-NMR (500 MHz,DMSO): 11.50 (s, 1H), 8.62 (s, 1H), 8.15 (s, 1H), 7.56 (s, 1H), 7.07 (d,1H), 7.0 (d, 1H), 6.92 (s, 2H), 6.71 (m, 1 H), 6.68 (s, 2H), 4.16 (m,2H), 3.71 (m, 2H), 3.01 (d, 2H), 2.30 (t, 2H), 2.14 (s, 6H), 1.10 (d,6H).

Example 16 Synthesis of5-((4-hydroxy-3,5-dimethylbenzyl)amino)-3-((4-(pyridin-3-yl)phenyl)amino)-1H-pyrazole-4-carboxamide16

The intermediate5-amino-3-((4-(pyridin-3-yl)phenyl)amino)-1H-pyrazole-4-carboxamide wasprepared in a manner substantially similar to that described for A2 ofExample 1.

5-amino-3-((4-(pyridin-3-yl)phenyl)amino)-1H-pyrazole-4-carboxamide(0.330 g) was suspended in EtOH (20 mL) and piperidine (5 drops). Thereaction mixture was heated at 80° C. while stirring, and3,5-dimethyl-4-hydroxybenzaldehyde (0.250 g) was added. After 18 h, thereaction mixture was cooled to room temperature. The separated solidswas collected by suction filtration and rinsed with ethanol to give thecrude imine product which was used without purification.

To a suspension of imine (64 mg) in DMF (6 mL) and MeOH (3 mL) wasslowly added sodium borohydride (10 mg) at room temperature. After thereaction mixture was stirred at room temperature for 1 hr, water wasadded and the resulting solid was collected by suction filtration. Therecovered precipitate was dissolved in DMSO, filtered through a cottonplug, which was further rinsed with EtOH. The DMSO and EtOH filtrateswere combined, and water was added until a precipitate formed. Theresulting suspension was chilled in a refrigerator for 3 hours. Theresulting precipitate was filtered, washed with water, and dried toyield compound 16 (57 mg, 98.4% purity) as a powder. ¹H-NMR (500 MHz,DMSO): 11.57 (s, 1H), 8.83 (m, 1H), 8.79 (s, 1H), 8.46 (m, 1H), 8.16 (s,1H), 7.99 (m, 1H), 7.57 (d, J=9 Hz, 2H), 7.41 (m, 1H), 7.35 (d, J=9 Hz,2H), 6.93 (2H), 6.71 (m, 3H), 4.19 (d, J=6 Hz, 2H), 2.15 (s, 6H).

Example 17 Synthesis of3-((3-chloro-4-(4-isopropylpiperazin-1-yl)phenyl)amino)-5-((4-hydroxy-3,5-dimethylbenzyl)amino)-1H-pyrazole-4-carboxamide17

The intermediate5-amino-3-((3-chloro-4-(4-isopropylpiperazin-1-yl)phenyl)amino)-1H-pyrazole-4-carboxamidewas prepared in a manner substantially similar to that described for A2of Example 1.

5-amino-3-((3-chloro-4-(4-isopropylpiperazin-1-yl)phenyl)amino)-1H-pyrazole-4-carboxamide(0.460 g) was suspended in EtOH (8 mL) and piperidine (5 drops). Thereaction mixture was heated at 80° C. while stirring, and3,5-dimethyl-4-hydroxybenzaldehyde (0.270 g) was added. After 18 h, thereaction mixture was cooled to room temperature. The separated solidswas collected by suction filtration and rinsed with ethanol to give thecrude imine product which was used without purification.

To a suspension of imine (80 mg) in DMF (2 mL) and MeOH (1 mL) wasslowly added sodium borohydride (12 mg) at room temperature. After thereaction mixture was stirred at room temperature for 1 hr, water wasadded and the resulting solid was collected by suction filtration. Therecovered precipitate was dissolved in DMSO, filtered through a cottonplug, which was further rinsed with EtOH. The DMSO and EtOH filtrateswere combined, and water was added until a precipitate formed. Theresulting suspension was chilled in a refrigerator for 3 hours. Theresulting precipitate was filtered, washed with water, and dried toyield compound 17 (60 mg, 96.1% purity) as a powder. ¹H-NMR (500 MHz,DMSO): 11.95 (s, 1H), 8.57 (s, 1H), 8.14 (s, 1H), 7.54 (s, 1H), 7.01 (m,2H), 6.92 (s, 2H), 6.67 (m, 3H), 4.16 (d, J=6 Hz, 2H), 2.86 (s, 4H),2.68 (m, 1H), 2.57 (s, 4H), 2.14 (s, 6H), 1.00 (d, J=7 Hz, 6H).

Example 18 Synthesis of3-([1,1′-biphenyl]-4-ylamino)-5-((4-hydroxy-3,5-dimethylbenzyl)amino)-1H-pyrazole-4-carboxamide18

The intermediate5-amino-3-((3-chloro-4-(4-isopropylpiperazin-1-yl)phenyl)amino)-1H-pyrazole-4-carboxamidewas prepared in a manner substantially similar to that described for A2of Example 1.

3-([1,1′-biphenyl]-4-ylamino)-5-amino-1H-pyrazole-4-carboxamide (0.086g) was suspended in EtOH (10 mL) and acetic acid (0.5 mL). The reactionmixture was heated at 80° C. while stirring, and3,5-dimethyl-4-hydroxybenzaldehyde (0.270 g) was added. After 20 h, thereaction mixture was cooled to room temperature. The separated solidswas collected by suction filtration and rinsed with ethanol to give thecrude imine product which was used without purification. The crude iminewas combined with DMF (1 mL) and MeOH (1 mL) and treated with 2equivalents of sodium borohydride at room temperature. After 5 hours,water was added, and the separated precipitate was collected by suctionfilteration, washed with water, and dried to yield compound 18 (60 mg)as a powder. ¹H-NMR (500 MHz, DMSO): 11.54 (s, 1H), 8.71 (s, 1H), 8.15(s, 1H), 7.59 (d, 2H), 7.50 (s, 2H), 7.40 (t, 2H), 7.31 (d, 2H), 7.24(t, 1H), 6.93 (s, 2H), 6.69 (s, 3H), 4.19 (d, 2H), 2.15 (s, 6H).

Example 193-((4-(1H-imidazol-1-yl)phenyl)amino)-5-((4-hydroxy-3,5-dimethylbenzyl)amino)-1H-pyrazole-4-carboxamide19

The intermediate3-((4-(1H-imidazol-1-yl)phenyl)amino)-5-amino-1H-pyrazole-4-carboxamidewas prepared in a manner substantially similar to that described for A2of Example 1.

3-((4-(1H-imidazol-1-yl)phenyl)amino)-5-amino-1H-pyrazole-4-carboxamide(0.246 g) was suspended in EtOH (10 mL) and piperidine (5 drops). Thereaction mixture was heated at 80° C. while stirring, and 1.4equivalents of 3,5-dimethyl-4-hydroxybenzaldehyde was added. After 20 h,the reaction mixture was cooled to room temperature. The separatedsolids was collected by suction filtration and rinsed with ethanol togive the crude imine product which was used without purification. Thecrude imine was combined with DMF (1 mL) and MeOH (1 mL) and treatedwith 2 equivalents of sodium borohydride at room temperature. After 5hours, water was added, and the separated precipitate was collected bysuction filteration, washed with water, and dried to yield compound 19(25 mg) as a powder. ¹H-NMR (500 MHz, DMSO): 2.15 (s, 6H), 4.19 (d, 2H),6.70 (s, 3H), 6.93 (s, 2H), 7.05 (s, 1H), 7.35 (s, 2H), 7.42 (d, 2H),7.58 (s, 1H), 8.06 (s, 1H), 8.15 (s, 1H), 8.76 (s, 1H), 11.54 (s, 1H)

Example 20 Synthesis of5-((4-hydroxy-3,5-dimethylbenzyl)amino)-3-((4-methoxyphenyl)amino)-1H-pyrazole-4-carboxamide20

The intermediate5-amino-3-((4-methoxyphenyl)amino)-1H-pyrazole-4-carboxamide wasprepared in a manner substantially similar to that described for A2 ofExample 1.

5-amino-3-((4-methoxyphenyl)amino)-1H-pyrazole-4-carboxamide (160 mg)was suspended in EtOH (10 mL) and piperidine (5 drops). The reactionmixture was heated at 80° C. while stirring, and 1.4 equivalents of3,5-dimethyl-4-hydroxybenzaldehyde was added. After 24 h, the reactionmixture was cooled to room temperature. The separated solids wascollected by suction filtration and rinsed with ethanol to give thecrude imine product which was used without purification. The crude iminewas combined with DMF (1 mL) and MeOH (1 mL) and treated with 2equivalents of sodium borohydride at room temperature. After 5 hours,water was added, and the separated precipitate was collected by suctionfilteration, washed with water, and dried to yield compound 20 (20 mg)as a powder. ¹H-NMR (500 MHz, DMSO): 2.17 (s, 6H), 3.68 (s, 3H), 4.16(d, 2H), 6.64 (m, 3H), 6.77 (d, 2H), 6.92 (s, 2H), 7.18 (d, 2H), 8.14(s, 1H), 8.31 (s, 1H), 11.38 (s, 1H).

Example 21 Synthesis of3-((4-(tert-butyl)phenyl)amino)-5-((4-hydroxy-3,5-dimethylbenzyl)amino)-1H-pyrazole-4-carboxamide21

The intermediate5-amino-3-((4-(tert-butyl)phenyl)amino)-1H-pyrazole-4-carboxamide wasprepared in a manner substantially similar to that described for A2 ofExample 1.

5-amino-3-((4-(tert-butyl)phenyl)amino)-1H-pyrazole-4-carboxamide (98mg) was suspended in EtOH (10 mL) and piperidine (5 drops). The reactionmixture was heated at 80° C. while stirring, and 1.5 equivalents of3,5-dimethyl-4-hydroxybenzaldehyde was added. After 20 h, the reactionmixture was cooled to room temperature. The separated solids wascollected by suction filtration and rinsed with ethanol to give thecrude imine product which was used without purification. The crude iminewas combined with DMF (1 mL) and MeOH (1 mL) and treated with 2equivalents of sodium borohydride at room temperature. After 5 hours,water was added, and the separated precipitate was collected by suctionfilteration, washed with water, and dried to yield compound 21 (90 mg)as a powder. ¹H-NMR (500 MHz, DMSO): 1.23 (s, 9H), 2.14 (s, 6H), 4.17(d, 2H), 6.64 (m, 3H), 6.92 (s, 2H), 7.10 (m, 2H), 7.20 (d, 2H), 8.13(s, 1H), 8.40 (s, 1H), 11.53 (s, 1H).

Example 22 Synthesis of3-((1H-indazol-5-yl)amino)-5-((4-hydroxy-3,5-dimethylbenzyl)amino)-1H-pyrazole-4-carboxamide22

The intermediate3-((1H-indazol-5-yl)amino)-5-amino-1H-pyrazole-4-carboxamide wasprepared in a manner substantially similar to that described for A2 ofExample 1.

3-((1H-indazol-5-yl)amino)-5-amino-1H-pyrazole-4-carboxamide (99 mg) wassuspended in EtOH (10 mL) and piperidine (5 drops). The reaction mixturewas heated at 80° C. while stirring, and 1.5 equivalents of3,5-dimethyl-4-hydroxybenzaldehyde was added. After 20 h, the reactionmixture was cooled to room temperature. The separated solids wascollected by suction filtration and rinsed with ethanol to give thecrude imine product which was used without purification. The crude iminewas combined with DMF (1 mL) and MeOH (1 mL) and treated with 2equivalents of sodium borohydride at room temperature. After 5 hours,water was added, and the separated precipitate was collected by suctionfilteration, washed with water, and dried to yield compound 22 (112 mg)as a powder. ¹H-NMR (500 MHz, DMSO): 2.15 (s, 6H), 4.18 (d, 2H), 6.66(m, 3H), 6.93 (s, 2H), 7.12 (d, 1H), 7.37 (d, 2H), 7.66 (m, 1H), 7.86(s, 1H), 8.14 (m, 1h0, 8.47 (s, 1H), 11.43 (s, 1H), 12.75 (s, 1H).

Example 235-((4-hydroxy-3,5-dimethylbenzyl)amino)-3-((4-(4-methyl-[1,4′-bipiperidin]-1′-yl)phenyl)amino)-1H-pyrazole-4-carboxamide23

The intermediate5-amino-3-((4-(4-methyl-[1,4′-bipiperidin]-1′-yl)phenyl)amino)-1H-pyrazole-4-carboxamidewas prepared in a manner substantially similar to that described for A2of Example 1.

5-amino-3-((4-(4-methyl-[1,4′-bipiperidin]-1′-yl)phenyl)amino)-1H-pyrazole-4-carboxamide(99 mg) was suspended in EtOH (10 mL) and piperidine (5 drops). Thereaction mixture was heated at 80° C. while stirring, and 1.5equivalents of 3,5-dimethyl-4-hydroxybenzaldehyde was added. After 20 h,the reaction mixture was cooled to room temperature. The separatedsolids was collected by suction filtration and rinsed with ethanol togive the crude imine product which was used without purification. Thecrude imine was combined with DMF (1 mL) and MeOH (1 mL) and treatedwith 2 equivalents of sodium borohydride at room temperature. After 5hours, water was added, and the separated precipitate was collected bysuction filteration, washed with water, and dried to yield compound 23(112 mg) as a powder. ¹H-NMR (500 MHz, DMSO): 2.15 (s, 6H), 4.18 (d,2H), 6.66 (m, 3H), 6.93 (s, 2H), 7.12 (d, 1H), 7.37 (d, 2H), 7.66 (m,1H), 7.86 (s, 1H), 8.14 (m, 1h0, 8.47 (s, 1H), 11.43 (s, 1H), 12.75 (s,1H).

Example 24 Synthesis of5-((4-hydroxy-3,5-dimethylbenzyl)amino)-3-((4-(4-(pyrrolidine-1-carbonyl)piperazin-1-yl)phenyl)amino)-1H-pyrazole-4-carboxamide24

The intermediate5-amino-3-((4-(4-(pyrrolidine-1-carbonyl)piperazin-1-yl)phenyl)amino)-1H-pyrazole-4-carboxamidewas prepared in a manner substantially similar to that described for A2of Example 1.

5-amino-3-((4-(4-(pyrrolidine-1-carbonyl)piperazin-1-yl)phenyl)amino)-1H-pyrazole-4-carboxamide(60 mg) was suspended in EtOH (10 mL) and piperidine (5 drops). Thereaction mixture was heated at 80° C. while stirring, and 1.5equivalents of 3,5-dimethyl-4-hydroxybenzaldehyde was added. After 2days, the reaction mixture was cooled to room temperature. The separatedsolids was collected by suction filtration and rinsed with ethanol togive the crude imine product which was used without purification. Thecrude imine was combined with DMF (1 mL) and MeOH (2 mL) and treatedwith 2 equivalents of sodium borohydride at room temperature. After 6hours, water was added, and the separated precipitate was collected bysuction filteration, washed with water, and dried to yield compound 24(40 mg) as a powder. ¹H-NMR (500 MHz, DMSO): 11.38 (s, 1H), 8.28 (s,1H), 8.14 (s, 1H), 7.14 (d, 2H), 6.92 (s, 2H), 6.82 (d, 2H), 6.64 (s,3H), 4.16 (d, 2H), 3.28 (m, 8H), 2.97 (m, 4H), 2.14 (s, 6H), 1.75 (m,4H).

Example 253-((4-(4-fluoropiperidin-1-yl)phenyl)amino)-5-((4-hydroxy-3,5-dimethylbenzyl)amino)-1H-pyrazole-4-carboxamide25

The intermediate5-amino-3-((4-(4-fluoropiperidin-1-yl)phenyl)amino)-1H-pyrazole-4-carboxamidewas prepared in a manner substantially similar to that described for A2of Example 1.

5-amino-3-((4-(4-fluoropiperidin-1-yl)phenyl)amino)-1H-pyrazole-4-carboxamide(320 mg) was suspended in EtOH (15 mL) and acetic acid (1 mL). Thereaction mixture was heated at 80° C. while stirring, and 1.5equivalents of 3,5-dimethyl-4-hydroxybenzaldehyde was added. After 16hours, the reaction mixture was cooled to room temperature. Theseparated solids was collected by suction filtration and rinsed withethanol to give the crude imine product which was used withoutpurification. The crude imine was combined with DMF (2 mL) and MeOH (0.5mL) and treated with 2 equivalents of sodium borohydride at roomtemperature. After 1 hour, water was added, and the separatedprecipitate was collected by suction filteration, washed with water, anddried to yield compound 25 (92 mg) as a powder. ¹H-NMR (500 MHz, DMSO):11.37 (s, 1H), 8.27 (s, 1H), 8.14 (s, 1H), 7.13 (d, 2H), 6.92 (s, 2H),6.83 (d, 2H), 6.63 (m, 3H), 4.793 (m, 1H), 4.16 (d, 2H), 3.17 (m, 2H),2.94 (m, 2H), 2.14 (s, 6H), 1.95 (m, 2H), 7.80 (m, 2H).

Example 263-((6-((2R,6S)-2,6-dimethyltetrahydro-2H-pyran-4-yl)pyridin-3-yl)amino)-5-((4-hydroxy-3,5-dimethylbenzyl)amino)-1H-pyrazole-4-carboxamide26

The intermediate5-amino-3-((6-((2R,6S)-2,6-dimethyltetrahydro-2H-pyran-4-yl)pyridin-3-yl)amino)-1H-pyrazole-4-carboxamidewas prepared in a manner substantially similar to that described for A2of Example 1.

5-amino-3-((6-((2R,6S)-2,6-dimethyltetrahydro-2H-pyran-4-yl)pyridin-3-yl)amino)-1H-pyrazole-4-carboxamide(1.020 g) was suspended in EtOH (3 mL) and acetic acid (0.5 mL). Thereaction mixture was heated at 80° C. while stirring, and 1.5equivalents of 3,5-dimethyl-4-hydroxybenzaldehyde was added. After 12hours, the reaction mixture was cooled to room temperature. Theseparated solids were collected by suction filtration and rinsed withethanol to give the crude imine product which was used withoutpurification (0.955 g). The crude imine (0.056 g) was combined with DMF(2 mL) and MeOH (1 mL) and treated with 2 equivalents of sodiumborohydride at room temperature. After 30 minutes, water was added, andthe separated precipitate was collected by suction filteration, washedwith water, and dried to yield compound 26 (36 mg) as a powder. ¹H-NMR(500 MHz, DMSO): 11.35 (s, 1H), 8.27 (s, 1H), 8.15 (d, 2H), 7.64 (d,1H), 6.91 (s, 2H), 6.74 (d, 1H), 6.68 (m, 3H), 4.16 (d, 2H), 3.92 (d,2H), 3.62 (m, 2H), 2.25 (t, 3H), 2.14 (s, 6H), 1.14 (d, 6H).

Example 275-((4-hydroxy-3,5-dimethylbenzyl)amino)-3-((4-(piperidin-1-yl)phenyl)amino)-1H-pyrazole-4-carboxamide27

The intermediate5-amino-3-((4-(piperidin-1-yl)phenyl)amino)-1H-pyrazole-4-carboxamidewas prepared in a manner substantially similar to that described for A2of Example 1.

5-amino-3-((4-(piperidin-1-yl)phenyl)amino)-1H-pyrazole-4-carboxamide(89 mg) was suspended in EtOH (10 mL) and piperidine (5 drops). Thereaction mixture was heated at 80° C. while stirring, and 1.5equivalents of 3,5-dimethyl-4-hydroxybenzaldehyde was added. After 20hours, the reaction mixture was cooled to room temperature. Theseparated solids were collected by suction filtration and rinsed withethanol to give the crude imine product which was used withoutpurification. The crude imine was combined with DMF (1 mL) and MeOH (1mL) and treated with 2 equivalents of sodium borohydride at roomtemperature. After 5 hours, water was added, and the separatedprecipitate was collected by suction filteration, washed with water, anddried to yield compound 27 (36 mg) as a powder. ¹H-NMR (500 MHz, DMSO):11.37 (s, 1H), 8.23 (s, 1H), 8.14 (s, 1H), 7.11 (d, 2H), 6.92 (s, 2H),6.79 (d, 2H), 6.63 (s, 2H), 4.16 (d, 2H), 2.95 (, 5H), 2.14 (s, 6H),1.60 (m, 4H), 1.48 (m, 2H).

Example 28 Synthesis of3-((3-chloro-4-((2S,6R)-2,6-dimethylmorpholino)phenyl)amino)-5-((4-hydroxy-3,5-dimethylbenzyl)amino)-1H-pyrazole-4-carboxamide28

The intermediate5-amino-3-((3-chloro-4-((2S,6R)-2,6-dimethylmorpholino)phenyl)amino)-1H-pyrazole-4-carboxamidewas prepared in a manner substantially similar to that described for A2of Example 1.

5-amino-3-((3-chloro-4-((2S,6R)-2,6-dimethylmorpholino)phenyl)amino)-1H-pyrazole-4-carboxamide(235 mg) was suspended in EtOH (3 mL) and acetic acid (0.5 mL). Thereaction mixture was heated at 80° C. while stirring, and 1.5equivalents of 3,5-dimethyl-4-hydroxybenzaldehyde was added. After 5hours, the reaction mixture was cooled to room temperature. Theseparated solids were collected by suction filtration and rinsed withethanol to give the crude imine product which was used withoutpurification. The crude imine (55 mg) was combined with DMF (1 mL) andMeOH (0.5 mL) and treated with 2 equivalents of sodium borohydride atroom temperature. After 1 hour, water was added, and the separatedprecipitate was collected by suction filteration, washed with water, anddried to yield compound 28 (55 mg) as a powder. ¹H-NMR (500 MHz, DMSO):11.50 (s, 1H), 8.62 (s, 1H), 8.15 (s, 1H), 7.56 (s, 1H), 7.07 (d, 1H),7.0 (d, 1H), 6.92 (s, 2H), 6.71 (m, 1H), 6.68 (s, 2H), 4.16 (m, 2H),3.71 (m, 2H), 3.01 (d, 2H), 2.30 (t, 2H), 2.14 (s, 6H), 1.10 (d, 6H).

Example 29 Synthesis of5-((4-hydroxy-3,5-dimethylbenzyl)amino)-3-((3-methyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-1H-pyrazole-4-carboxamide29

The intermediate5-amino-3-((3-methyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-1H-pyrazole-4-carboxamidewas prepared in a manner substantially similar to that described for A2of Example 1.

5-amino-3-((3-methyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-1H-pyrazole-4-carboxamide(420 mg) was suspended in EtOH (10 mL) and acetic acid (0.5 mL). Thereaction mixture was heated at 80° C. while stirring, and 1.5equivalents of 3,5-dimethyl-4-hydroxybenzaldehyde was added. After 16hours, the reaction mixture was cooled to room temperature. Theseparated solids were collected by suction filtration and rinsed withethanol to give the crude imine product (0.650 g) which was used withoutpurification. The crude imine (87 mg) was combined with DMF (1 mL) andMeOH (0.5 mL) and treated with 2 equivalents of sodium borohydride atroom temperature. After 1 hour, water was added, and the separatedprecipitate was collected by suction filteration, washed with water, anddried to yield compound 29 (87 mg) as a powder. ¹H-NMR (500 MHz, DMSO):11.42 (s, 1H), 8.33 (s, 1H), 8.14 (s, 1H), 7.03 (m, 2H), 6.92 (s, 2H),6.88 (d, 1H), 6.64 (s, 3H), 4.16 (m, 2H), 2.88 (m, 1H), 2.74 (m, 4H),2.44 (m, 3H), 2.19 (3H), 2.15 (m, 9H).

Example 30 Synthesis of5-((4-hydroxy-3,5-dimethylbenzyl)amino)-3-((3-methyl-4-(piperidin-1-yl)phenyl)amino)-1H-pyrazole-4-carboxamide30

The intermediate5-amino-3-((3-methyl-4-(piperidin-1-yl)phenyl)amino)-1H-pyrazole-4-carboxamidewas prepared in a manner substantially similar to that described for A2of Example 1.

5-amino-3-((3-methyl-4-(piperidin-1-yl)phenyl)amino)-1H-pyrazole-4-carboxamide(240 mg) was suspended in EtOH (10 mL) and acetic acid (0.5 mL). Thereaction mixture was heated at 80° C. while stirring, and 1.5equivalents of 3,5-dimethyl-4-hydroxybenzaldehyde was added. After 16hours, the reaction mixture was cooled to room temperature. Theseparated solids were collected by suction filtration and rinsed withethanol to give the crude imine product (0.240 g) which was used withoutpurification. The crude imine (51 mg) was combined with DMF (1 mL) andMeOH (0.5 mL) and treated with 2 equivalents of sodium borohydride atroom temperature. After 1 hour, water was added, and the separatedprecipitate was collected by suction filteration, washed with water, anddried to yield compound 30 (51 mg) as a powder. ¹H-NMR (500 MHz, DMSO):11.41 (s, 1H), 8.302 (s, 1H), 8.14 (s, 1H), 7.05 (s, 1H), 6.94 (m, 1H),6.92 (s, 2H), 6.86 (m, 1H), 6.64 (s, 3H), 4.16 (m, 2H), 2.68 (m, 4H),2.15 (m, 9H), 1.61 (m, 4H), 1.49 (m, 2H).

Example 31 Synthesis of3-((4-(4-benzylpiperazin-1-yl)phenyl)amino)-5-((4-hydroxy-3,5-dimethylbenzyl)amino)-1H-pyrazole-4-carboxamide31

The intermediate5-amino-3-((4-(4-benzylpiperazin-1-yl)phenyl)amino)-1H-pyrazole-4-carboxamidewas prepared in a manner substantially similar to that described for A2of Example 1.

5-amino-3-((4-(4-benzylpiperazin-1-yl)phenyl)amino)-1H-pyrazole-4-carboxamide(240 mg) was suspended in EtOH (5 mL) and acetic acid (0.5 mL). Thereaction mixture was heated at 80° C. while stirring, and 1.4equivalents of 3,5-dimethyl-4-hydroxybenzaldehyde was added. After 5hours, the reaction mixture was cooled to room temperature. Theseparated solids were collected by suction filtration and rinsed withethanol to give the crude imine product (0.489 g) which was used withoutpurification. The crude imine (116 mg) was combined with DMF (1 mL) andMeOH (1 mL) and treated with 2 equivalents of sodium borohydride at roomtemperature. After 30 minutes, water was added, and the separatedprecipitate was collected by suction filteration, washed with water, anddried to yield compound 31 (92 mg) as a powder. ¹H-NMR (500 MHz, DMSO):11.37 (s, 1H), 8.25 (s, 1H), 8.14 (s, 1H), 7.31 (m, 4H), 7.25 (m, 1H),7.13 (d, 2H), 6.91 (s, 2H), 6.79 (d, 2H), 6.63 (s, 3H), 4.16 (d, 2H),3.51 (s, 2H), 2.99 (s, 4H), 2.14 (s, 6H).

Example 32 Synthesis of3-((4-(1,1-dioxidothiomorpholino)phenyl)amino)-5-((4-hydroxy-3,5-dimethylbenzyl)amino)-1H-pyrazole-4-carboxamide32

The intermediate5-amino-3-((4-(1,1-dioxidothiomorpholino)phenyl)amino)-1H-pyrazole-4-carboxamidewas prepared in a manner substantially similar to that described for A2of Example 1.

5-amino-3-((4-(1,1-dioxidothiomorpholino)phenyl)amino)-1H-pyrazole-4-carboxamide(108 mg) was suspended in EtOH (5 mL) and acetic acid (0.5 mL). Thereaction mixture was heated at 80° C. while stirring, and 1.4equivalents of 3,5-dimethyl-4-hydroxybenzaldehyde was added. After 5hours, the reaction mixture was cooled to room temperature. Theseparated solids were collected by suction filtration and rinsed withethanol to give the crude imine product (0.240 g) which was used withoutpurification. The crude imine (51 mg) was combined with DMF (6 mL) andMeOH (3 mL) and treated with 2 equivalents of sodium borohydride at roomtemperature. After 30 minutes, water was added, and the separatedprecipitate was collected by suction filteration, washed with water, anddried to yield compound 32 (73 mg) as a powder. ¹H-NMR (500 MHz, DMSO):11.40 (s, 1H), 8.34 (s, 1H), 8.16 (s, 1H), 7.17 (s, 1H), 6.90 (m, 4H),6.65 (s, 2H), 4.16 (d, 2H), 3.58 (s, 4H), 3.12 (m, 4H), 2.14 (s, 6H).

Example 33 Synthesis of5-((4-hydroxy-3,5-dimethylbenzyl)amino)-3-((5-(piperidin-1-yl)pyridin-2-yl)amino)-1H-pyrazole-4-carboxamide33

The intermediate5-amino-3-((5-(piperidin-1-yl)pyridin-2-yl)amino)-1H-pyrazole-4-carboxamidewas prepared in a manner substantially similar to that described for A2of Example 1.

5-amino-3-((5-(piperidin-1-yl)pyridin-2-yl)amino)-1H-pyrazole-4-carboxamide(167 mg) was suspended in EtOH (10 mL) and acetic acid (0.5 mL). Thereaction mixture was heated at 80° C. while stirring, and 1.5equivalents of 3,5-dimethyl-4-hydroxybenzaldehyde was added. After 16hours, the reaction mixture was cooled to room temperature. Theseparated solids were collected by suction filtration and rinsed withethanol to give the crude imine product, which was used withoutpurification. The crude imine was combined with DMF (1 mL) and MeOH (0.5mL) and treated with 2 equivalents of sodium borohydride at roomtemperature. After 1 hour, water was added, and the separatedprecipitate was collected by suction filteration, washed with water, anddried to yield compound 33 (150 mg) as a powder. ¹H-NMR (500 MHz, DMSO):11.66 (m, 1H), 9.35 (m, 1H), 8.13 (s, 1H), 7.81 (m, 1H), 7.55 (d, 1H),7.29 (m, 1H), 6.91 (s, 2H), 6.68 (s, 2H), 6.41 (m, 1H), 4.15 (m, 2H),2.98 (m, 4H), 2.13 (s, 6H), 1.61 (m, 4H), 1.48 (m, 2H).

Example 34 Synthesis of3-((4-(4-chloropiperidin-1-yl)phenyl)amino)-5-((4-hydroxy-3,5-dimethylbenzyl)amino)-1H-pyrazole-4-carboxamide34

The intermediate5-amino-3-((4-(4-chloropiperidin-1-yl)phenyl)amino)-1H-pyrazole-4-carboxamidewas prepared in a manner substantially similar to that described for A2of Example 1.

5-amino-3-((4-(4-chloropiperidin-1-yl)phenyl)amino)-1H-pyrazole-4-carboxamide(167 mg) was suspended in EtOH (10 mL) and piperidine (5 drops). Thereaction mixture was heated at 80° C. while stirring, and 1.5equivalents of 3,5-dimethyl-4-hydroxybenzaldehyde was added. After 16hours, the reaction mixture was cooled to room temperature. Theseparated solids were collected by suction filtration and rinsed withethanol to give the crude imine product (0.320 g), which was usedwithout purification. The crude imine (52 mg) was combined with DMF (0.5mL) and MeOH (2 mL) and treated with 2 equivalents of sodium borohydrideat room temperature. After 1 hour, water was added, and the separatedprecipitate was collected by suction filteration, washed with water, anddried to yield compound 34 (52 mg) as a powder. ¹H-NMR (500 MHz, DMSO):11.38 (s, 1H), 8.27 (s, 1H), 8.14 (s, 1H), 7.13 (d, 2H), 6.92 (s, 2H),6.82 (d, 2H), 6.64 (m, 3H), 4.33 (m, 1H), 4.16 (d, 2H), 2.87 (m, 2H),2.13 (m, 10H), 1.86 (m, 2H).

Example 35 Synthesis of5-((4-hydroxy-3,5-dimethylbenzyl)amino)-3-((4-(pyrrolidin-1-ylmethyl)phenyl)amino)-1H-pyrazole-4-carboxamide35

The intermediate5-amino-3-((4-(pyrrolidin-1-ylmethyl)phenyl)amino)-1H-pyrazole-4-carboxamidewas prepared in a manner substantially similar to that described for A2of Example 1.

5-amino-3-((4-(pyrrolidin-1-ylmethyl)phenyl)amino)-1H-pyrazole-4-carboxamide(400 mg) was suspended in EtOH (5 mL) and piperidine (5 drops mL). Thereaction mixture was heated at 80° C. while stirring, and 1.5equivalents of 3,5-dimethyl-4-hydroxybenzaldehyde was added. After 16hours, the reaction mixture was cooled to room temperature. Theseparated solids were collected by suction filtration and rinsed withethanol to give the crude imine product (0.420 g), which was usedwithout purification. The crude imine (0.182 g) was combined with DMF (6mL) and MeOH (3 mL) and treated with 2 equivalents of sodium borohydrideat room temperature. After 30 minutes, water was added, and theseparated precipitate was collected by suction filteration, washed withwater, and dried to yield compound 35 (123 mg) as a powder. ¹H-NMR (500MHz, DMSO): 11.48 (s, 1H), 8.50 (s, 1H), 8.14 (s, 1H), 7.10 (m, 4H),6.92 (s, 2H), 6.65 (s, 2H), 4.17 (d, 2H), 3.43 (s, 2H), 3.38 (m, 4H),2.15 (s, 6H), 1.66 (m, 4H).

Example 36 Synthesis of3-((4-(4-(dimethylamino)piperidin-1-yl)phenyl)amino)-5-((4-hydroxy-3,5-dimethylbenzyl)amino)-1H-pyrazole-4-carboxamide36

The intermediate5-amino-3-((4-(4-(dimethylamino)piperidin-1-yl)phenyl)amino)-1H-pyrazole-4-carboxamidewas prepared in a manner substantially similar to that described for A2of Example 1.

5-amino-3-((4-(4-(dimethylamino)piperidin-1-yl)phenyl)amino)-1H-pyrazole-4-carboxamide(300 mg) was suspended in EtOH (8 mL) and piperidine (5 drops). Thereaction mixture was heated at 80° C. while stirring, and 1.5equivalents of 3,5-dimethyl-4-hydroxybenzaldehyde was added. After 16hours, the reaction mixture was cooled to room temperature. Theseparated solids were collected by suction filtration and rinsed withethanol to give the crude imine product (0.470 g), which was usedwithout purification. The crude imine (50 mg) was combined with DMF (2mL) and MeOH (2 mL) and treated with 2 equivalents of sodium borohydrideat room temperature. After 2 hours, water was added, and the separatedprecipitate was collected by suction filteration, washed with water, anddried to yield compound 36 (150 mg) as a powder.

Example 37 Synthesis of3-((3-fluoro-4-morpholinophenyl)amino)-5-((4-hydroxy-3,5-dimethylbenzyl)amino)-1H-pyrazole-4-carboxamide37

The intermediate3-((3-fluoro-4-morpholinophenyl)amino)-5-((4-hydroxy-3,5-dimethylbenzyl)amino)-1H-pyrazole-4-carboxamidewas prepared in a manner substantially similar to that described for A2of Example 1.

3-((3-fluoro-4-morpholinophenyl)amino)-5-((4-hydroxy-3,5-dimethylbenzyl)amino)-1H-pyrazole-4-carboxamide(400 mg) was suspended in EtOH (5 mL) and piperidin (5 drops). Thereaction mixture was heated at 80° C. while stirring, and 1.4equivalents of 3,5-dimethyl-4-hydroxybenzaldehyde was added. After 20hours, the reaction mixture was cooled to room temperature. Theseparated solids were collected by suction filtration and rinsed withethanol to give the crude imine product, which was used withoutpurification. Some of the crude imine (97 mg) was combined with DMF (1mL) and MeOH (4 mL) and treated with 2 equivalents of sodium borohydrideat room temperature. After 15 minutes, water was added, and theseparated precipitate was collected by suction filteration, washed withwater, and dried to yield compound 37 (75 mg) as a powder. ¹H-NMR (500MHz, DMSO): 2.14 (s, 6H), 2.88 (t, 4H), 3.70 (t, 4H), 4.17 (d, 2H), 6.68(m, 3H), 6.90 (m, 4H), 7.28 (d, 1H), 8.15 (s, 1H), 8.61 (s, 1H), 11.47(s, 1H).

Example 38 Synthesis of5-((4-hydroxy-3,5-dimethylbenzyl)amino)-3-((4-(oxazol-5-yl)phenyl)amino)-1H-pyrazole-4-carboxamide38

The intermediate5-amino-3-((4-(oxazol-5-yl)phenyl)amino)-1H-pyrazole-4-carboxamide wasprepared in a manner substantially similar to that described for A2 ofExample 1.

5-amino-3-((4-(oxazol-5-yl)phenyl)amino)-1H-pyrazole-4-carboxamide (176mg) was suspended in EtOH (5 mL) and piperidine (5 drops). The reactionmixture was heated at 80° C. while stirring, and 1.4 equivalents of3,5-dimethyl-4-hydroxybenzaldehyde was added. After 18 hours, thereaction mixture was cooled to room temperature. The separated solidswere collected by suction filtration and rinsed with ethanol to give thecrude imine product, which was combined with DMF (1 mL) and MeOH (1 mL)and treated with 2 equivalents of sodium borohydride at roomtemperature. After 1 hour, water was added, and the separatedprecipitate was collected by suction filteration, washed with water, anddried to yield compound 38 (33 mg) as a powder. ¹H-NMR (500 MHz, DMSO):2.15 (s, 6H), 4.18 (d, 2H), 6.70 (m, 3H), 6.93 (s, 2H), 7.33 (d, 2H),7.43 (s, 1H), 7.54 (d, 2H), 8.15 (s, 1H), 8.31 (s, 1H), 8.88 (s, 1H),11.57 (s, 1H).

Example 39 Synthesis of5-((4-hydroxy-3,5-dimethylbenzyl)amino)-3-((4-(4-(morpholine-4-carbonyl)piperazin-1-yl)phenyl)amino)-1H-pyrazole-4-carboxamide39

The intermediate5-amino-3-((4-(4-(morpholine-4-carbonyl)piperazin-1-yl)phenyl)amino)-1H-pyrazole-4-carboxamidewas prepared in a manner substantially similar to that described for A2of Example 1.

5-amino-3-((4-(4-(morpholine-4-carbonyl)piperazin-1-yl)phenyl)amino)-1H-pyrazole-4-carboxamide(210 mg) was suspended in EtOH (15 mL) and piperidine (5 drops). Thereaction mixture was heated at 80° C. while stirring, and 1.4equivalents of 3,5-dimethyl-4-hydroxybenzaldehyde was added. After 24hours, the reaction mixture was cooled to room temperature. Theseparated solids were collected by suction filtration and rinsed withethanol to give the crude imine product, which was used withoutpurification. The crude imine was combined with DMF (1 mL) and MeOH (2mL) and treated with 2 equivalents of sodium borohydride at roomtemperature. After 30 minutes, water was added, and the separatedprecipitate was collected by suction filteration, washed with water, anddried to yield compound 39 (41 mg) as a powder. ¹H-NMR (500 MHz, DMSO):11.38 (s, 1H), 8.28 (s, 1H), 8.14 (s, 1H), 7.14 (d, 2H), 6.92 (s, 2H),6.82 (d, 2H), 6.63 (m, 3H), 4.16 (d, 2H), 3.57 (t, 4H), 3.28 (t, 4H),3.16 (t, 4H), 2.89 (t, 4H), 2.14 (s, 6H).

Example 40 Synthesis of3-((3-acetamidophenyl)amino)-5-((4-hydroxy-3,5-dimethylbenzyl)amino)-1H-pyrazole-4-carboxamide40

The intermediate3-((3-acetamidophenyl)amino)-5-amino-1H-pyrazole-4-carboxamide wasprepared in a manner substantially similar to that described for A2 ofExample 1.

3-((3-acetamidophenyl)amino)-5-amino-1H-pyrazole-4-carboxamide (100 mg)was suspended in EtOH (8 mL) and piperidine (5 drops). The reactionmixture was heated at 80° C. while stirring, and 1.5 equivalents of3,5-dimethyl-4-hydroxybenzaldehyde was added. After 16 hours, thereaction mixture was cooled to room temperature. The separated solidswere collected by suction filtration and rinsed with ethanol to give thecrude imine product, which was used without purification. The crudeimine was combined with DMF (1 mL) and MeOH (2 mL) and treated with 2equivalents of sodium borohydride at room temperature. After 1 hour,water was added, and the mixture was extracted with ethyl acetate,washed with water and saturated NaCl solution, dried over anhydroussodium sulfate and evaporated to give a crude solid. The crude solidewas recrystallized from acetone and water to yield compound 40 (68 mg).¹H-NMR (500 MHz, DMSO): 11.53 (s, 1H), 9.75 (s, 1H), 8.46 (s, 1H), 8.15(s, 1H), 7.33 (s, 1H), 7.06 (t, 2H), 6.92 (m, 3H), 6.65 (m, 3H), 4.18(d, 2H), 2.15 (s, 6H), 2.00 (s, 3H).

Example 41 Synthesis of3-((3-chloro-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-((4-hydroxy-3,5-dimethylbenzyl)amino)-1H-pyrazole-4-carboxamide41

The intermediate5-amino-3-((3-chloro-4-(4-methylpiperazin-1-yl)phenyl)amino)-1H-pyrazole-4-carboxamidewas prepared in a manner substantially similar to that described for A2of Example 1.

5-amino-3-((3-chloro-4-(4-methylpiperazin-1-yl)phenyl)amino)-1H-pyrazole-4-carboxamide(370 mg) was suspended in EtOH (10 mL) and piperidine (3 drops). Thereaction mixture was heated at 80° C. while stirring, and 1.4equivalents of 3,5-dimethyl-4-hydroxybenzaldehyde was added. After 17hours, the reaction mixture was cooled to room temperature. Theseparated solids were collected by suction filtration and rinsed withethanol to give the crude imine product (487 mg), which was used withoutpurification. The crude imine (82 mg) was combined with DMF (2 mL) andMeOH (2 mL) and treated with 2 equivalents of sodium borohydride at roomtemperature. After 30 minutes, water was added, and the separatedprecipitate was collected by suction filteration, washed with water, anddried to yield compound 41 (65 mg) as a powder. ¹H-NMR (500 MHz, DMSO):11.50 (s, 1H), 8.59 (s, 1H), 8.15 (s, 1H), 7.55 (s, 1H), 7.02 (m, 2H),6.92 (s, 2H), 6.69 (m, 3H), 4.16 (d, 2H), 2.86 (m, 4H), 2.45 (m, 4H),2.21 (s, 3H), 2.14 (s, 6H).

Example 42 Synthesis of3-((4-fluorophenyl)amino)-5-((4-hydroxy-3,5-dimethylbenzyl)amino)-1H-pyrazole-4-carboxamide42

The intermediate5-amino-3-((4-fluorophenyl)amino)-1H-pyrazole-4-carboxamide was preparedin a manner substantially similar to that described for A2 of Example 1.

5-amino-3-((4-fluorophenyl)amino)-1H-pyrazole-4-carboxamide (225 mg) wassuspended in EtOH (5 mL) and piperidine (5 drops). The reaction mixturewas heated at 80° C. while stirring, and 1.4 equivalents of3,5-dimethyl-4-hydroxybenzaldehyde was added. After 22 hours, thereaction mixture was cooled to room temperature. The separated solidswere collected by suction filtration and rinsed with ethanol to give thecrude imine product (342 mg), which was used without purification. Thecrude imine (70 mg) was combined with DMF (1 mL) and MeOH (1 mL) andtreated with 2 equivalents of sodium borohydride at room temperature.After 3 hours, water was added, and the separated precipitate wascollected by suction filteration, washed with water, and dried to yieldcompound 42 (63 mg) as a powder. ¹H-NMR (500 MHz, DMSO): 11.46 (s, 1H),8.54 (s, 1H), 8.14 (s, 1H), 7.25 (m, 2H), 7.00 (t, 2H), 6.92 (s, 2H),6.67 (m, 3H), 4.17 (d, 2H), 2.15 (s, 6H).

Example 43 Synthesis of3-((3-cyanophenyl)amino)-5-((4-hydroxy-3,5-dimethylbenzyl)amino)-1H-pyrazole-4-carboxamide43

The intermediate5-amino-3-((3-cyanophenyl)amino)-1H-pyrazole-4-carboxamide was preparedin a manner substantially similar to that described for A2 of Example 1.

5-amino-3-((3-cyanophenyl)amino)-1H-pyrazole-4-carboxamide (250 mg) wassuspended in EtOH (5 mL) and piperidine (5 drops). The reaction mixturewas heated at 80° C. while stirring, and 1.4 equivalents of3,5-dimethyl-4-hydroxybenzaldehyde was added. After 22 hours, thereaction mixture was cooled to room temperature. The separated solidswere collected by suction filtration and rinsed with ethanol to give thecrude imine product (342 mg), which was used without purification. Thecrude imine (64 mg) was combined with DMF (1 mL) and MeOH (1 mL) andtreated with 2 equivalents of sodium borohydride at room temperature.After 3 hours, water was added, and the separated precipitate wascollected by suction filteration, washed with water, and dried to yieldcompound 43 (47 mg) as a powder. ¹H-NMR (500 MHz, DMSO): 9.01 (s, 1H),8.15 (s, 1H), 7.84 (s, 1H), 7.46 (d, 1H), 7.36 (t, 1H), 7.16 (d, 2H),6.93 (s, 2H), 6.74 (m, 3H), 4.18 (d, 2H), 2.15 (s, 6H).

Example 44 Synthesis of5-((4-hydroxy-3,5-dimethylbenzyl)amino)-3-((4-(4-(pyrimidin-2-yl)piperazin-1-yl)phenyl)amino)-1H-pyrazole-4-carboxamide44

The intermediate5-amino-3-((4-(4-(pyrimidin-2-yl)piperazin-1-yl)phenyl)amino)-1H-pyrazole-4-carboxamidewas prepared in a manner substantially similar to that described for A2of Example 1.

5-amino-3-((4-(4-(pyrimidin-2-yl)piperazin-1-yl)phenyl)amino)-1H-pyrazole-4-carboxamide(104.4 mg) was suspended in EtOH (5 mL) and piperidine (5 drops). Thereaction mixture was heated at 80° C. while stirring, and 1.5equivalents of 3,5-dimethyl-4-hydroxybenzaldehyde was added. After 24hours, the reaction mixture was cooled to room temperature. Theseparated solids were collected by suction filtration and rinsed withethanol to give the crude imine product (141 mg), which was used withoutpurification. The crude imine (109 mg) was combined with DMF (1 mL) andMeOH (3 mL) and treated with 2 equivalents of sodium borohydride at roomtemperature. After 18 hours, water was added, and the separatedprecipitate was collected by suction filteration, washed with water, anddried to yield compound 44 (109 mg) as a powder. ¹H-NMR (500 MHz, DMSO):11.38 (s, 1H), 8.38 (m, 2H), 8.29 (s, 1H), 8.13 (s, 1H), 7.16 (d, 2H),6.92 (s, 2H), 6.87 (d, 2H), 6.64 (m, 4H), 4.16 (d, 2H), 3.86 (t, 4H),3.05 (t, 4H), 2.14 (s, 6H).

Example 45 Synthesis of5-((4-hydroxy-3,5-dimethylbenzyl)amino)-3-((4-(piperidin-1-ylmethyl)phenyl)amino)-1H-pyrazole-4-carboxamide45

The intermediate5-amino-3-((4-(piperidin-1-ylmethyl)phenyl)amino)-1H-pyrazole-4-carboxamidewas prepared in a manner substantially similar to that described for A2of Example 1.

5-amino-3-((4-(piperidin-1-ylmethyl)phenyl)amino)-1H-pyrazole-4-carboxamide(150 mg) was suspended in EtOH (3 mL) and piperidine (0.5 mL). Thereaction mixture was heated at 80° C. while stirring, and 1.4equivalents of 3,5-dimethyl-4-hydroxybenzaldehyde was added. After 18hours, the reaction mixture was cooled to room temperature. Theseparated solids were collected by suction filtration and rinsed withethanol to give the crude imine product (145 mg), which was used withoutpurification. The crude imine (100 mg) was combined with DMF (2 mL) andMeOH (1 mL) and treated with 2 equivalents of sodium borohydride at roomtemperature. After 30 minutes, water was added, and the separatedprecipitate was collected by suction filteration, washed with water, anddried to yield compound 45 (100 mg) as a powder. ¹H-NMR (500 MHz, DMSO):11.48 (s, 1H), 7.14 (s, 2H), 7.06 (d, 2H), 6.92 (s, 2H), 6.65 (s, 3H),4.17 (s, 2H), 3.28 (s, 4H), 2.27 (s, 4H), 2.14 (s, 6H), 1.46 (m, 4H),1.36 (m, 2H).

Example 46 Synthesis of5-((4-hydroxy-3,5-dimethylbenzyl)amino)-3-((4-thiomorpholinophenyl)amino)-1H-pyrazole-4-carboxamide46

The intermediate5-amino-3-((4-thiomorpholinophenyl)amino)-1H-pyrazole-4-carboxamide wasprepared in a manner substantially similar to that described for A2 ofExample 1.

5-amino-3-((4-thiomorpholinophenyl)amino)-1H-pyrazole-4-carboxamide (389mg) was suspended in EtOH (10 mL) and acetic acid (0.5 mL). The reactionmixture was heated at 80° C. while stirring, and 1.5 equivalents of3,5-dimethyl-4-hydroxybenzaldehyde was added. After 16 hours, thereaction mixture was cooled to room temperature. The separated solidswere collected by suction filtration and rinsed with ethanol to give thecrude imine product (497 mg), which was used without purification. Thecrude imine (135 mg) was combined with DMF (6 mL) and MeOH (2 mL) andtreated with 2 equivalents of sodium borohydride at room temperature.After 30 minutes, water was added, and the crude product was tituratedwith EtOH at 80° C. for 1 hour. The precipitate was collected by suctionfilteration, washed with EtOH, and dried to yield compound 46 (105 mg)as a powder. ¹H-NMR (500 MHz, DMSO): 11.38 (s, 1H), 8.29 (s, 1H), 8.149s, 1H), 7.14 (d, 2H), 6.92 (s, 2H), 6.81 (d, 2H), 6.63 (m, 3H), 4.16(d, 2H), 3.28 (m, 4H), 2.68 (m, 4H), 2.14 (s, 6H).

Example 47 Synthesis of3-((4-aminophenyl)amino)-5-((4-hydroxy-3,5-dimethylbenzyl)amino)-1H-pyrazole-4-carboxamide47

The intermediate5-amino-3-((4-nitrophenyl)amino)-1H-pyrazole-4-carboxamide was preparedin a manner substantially similar to that described for A2 of Example 1.

5-amino-3-((4-nitrophenyl)amino)-1H-pyrazole-4-carboxamide (1.006 g) wassuspended in EtOH (3 mL) and piperidine (5 drops). The reaction mixturewas heated at 80° C. while stirring, and 1.5 equivalents of3,5-dimethyl-4-hydroxybenzaldehyde was added. After 24 hours, thereaction mixture was cooled to room temperature. The separated solidswere collected by suction filtration and rinsed with ethanol to give thecrude imine product (1.308 g) which was used without purification. Thecrude imine (100 mg) was combined with DMF (0.5 mL) and MeOH (1 mL) andtreated with 2 equivalents of sodium borohydride at room temperature.After 2 hours, water was added, and the separated precipitate wascollected by suction filteration, washed with water. This precipitatewas dissolved in MeOH (1 mL) and THF (2 mL), treated with 10% Palladiumon Carbon (20 mg) and stirred under a hydrogen atmosphere (30 psi). Thesuspension was collected by suction and then recrystallized from DMSOand water to yield compound 47 (18 mg). ¹H-NMR (500 MHz, DMSO): 11.28(s, 1H), 8.13 (s, 1H), 8.00 (s, 1H), 6.91 (s, 4H), 6.60 (s, 3H), 6.46(d, J=9, 2H), 4.50 (s, 2H), 4.15 (d, J=6, 2H), 2.14 (s, 6H).

Example 48 Synthesis of5-((4-hydroxy-3,5-dimethylbenzyl)amino)-3-((4-sulfamoylphenyl)amino)-1H-pyrazole-4-carboxamide48

The intermediate5-amino-3-((4-sulfamoylphenyl)amino)-1H-pyrazole-4-carboxamide wasprepared in a manner substantially similar to that described for A2 ofExample 1.

5-amino-3-((4-sulfamoylphenyl)amino)-1H-pyrazole-4-carboxamide (230 mg)was suspended in EtOH (5 mL) and piperidine (5 drops). The reactionmixture was heated at 80° C. while stirring, and 1.5 equivalents of3,5-dimethyl-4-hydroxybenzaldehyde was added. After 60 hours, thereaction mixture was cooled to room temperature. The separated solidswere collected by suction filtration and rinsed with ethanol to give thecrude imine, which was combined with DMF (1 mL) and MeOH (3 mL) andtreated with 2 equivalents of sodium borohydride at room temperature.After 30 minutes, water was added, and the separated precipitate wascollected by suction filteration, washed with water, and dried to yieldcompound 48 (244 mg) as a powder. ¹H-NMR (500 MHz, DMSO): 11.65 (s, 1H),9.08 (s, 1H), 8.16 (s, 1H), 7.62 (d, J=9, 2H), 7.31 (d, J=9, 2H), 7.05(s, 2H), 6.93 (s, 2H), 6.73 (m, 3H), 4.18 (d, J=6, 2H), 2.15 (s, 6H).

Example 49 Synthesis of5-((4-hydroxy-3,5-dimethylbenzyl)amino)-3-((6-(4-(pyrrolidin-1-yl)piperidin-1-yl)pyridin-3-yl)amino)-1H-pyrazole-4-carboxamide49

The intermediate5-amino-3-((6-(4-(pyrrolidin-1-yl)piperidin-1-yl)pyridin-3-yl)amino)-1H-pyrazole-4-carboxamidewas prepared in a manner substantially similar to that described for A2of Example 1.

5-amino-3-((6-(4-(pyrrolidin-1-yl)piperidin-1-yl)pyridin-3-yl)amino)-1H-pyrazole-4-carboxamide(46 mg) was suspended in EtOH (5 mL) and piperidine (5 drops). Thereaction mixture was heated at 80° C. while stirring, and 1.5equivalents of 3,5-dimethyl-4-hydroxybenzaldehyde was added. After 36hours, the reaction mixture was cooled to room temperature. Theseparated solids were collected by suction filtration and rinsed withethanol to give the crude imine product, which was combined with DMF(1.5 mL) and MeOH (2.5 mL) and treated with 2 equivalents of sodiumborohydride at room temperature. After 48 hours, water was added, andthe separated precipitate was collected by suction filteration, washedwith water, and dried to yield compound 49 (29 mg) as a powder. ¹H-NMR(500 MHz, DMSO): 8.21 and 8.15 (s, s, 3H), 7.60 and 7.54 (d, s, 1H),6.91 (s, 1H), 6.81 and 6.73 (d, J=9 Hz, d, J=9 Hz, 1H), 6.69 and 6.66(s, s, 3H), 4.16, 4.05 and 3.99 (m, m, m, 4H), 2.74 (m, 3H), 2.14 (s,6H), 1.87 (d, J=10 Hz, 2H), 1.67 (s, 4H), 1.38 (m, 2H).

Example 50 Synthesis of3-((4-(dimethylamino)phenyl)amino)-5-((4-hydroxy-3,5-dimethylbenzyl)amino)-1H-pyrazole-4-carboxamide50

The intermediate5-amino-3-((4-(dimethylamino)phenyl)amino)-1H-pyrazole-4-carboxamide wasprepared in a manner substantially similar to that described for A2 ofExample 1.

5-amino-3-((4-(dimethylamino)phenyl)amino)-1H-pyrazole-4-carboxamide (95mg) was suspended in EtOH (5 mL) and piperidine (5 drops). The reactionmixture was heated at 80° C. while stirring, and 1.5 equivalents of3,5-dimethyl-4-hydroxybenzaldehyde was added. After 22 hours, thereaction mixture was cooled to room temperature. The separated solidswere collected by suction filtration and rinsed with ethanol to give thecrude imine product, which was combined with DMF (0.5 mL) and MeOH (2.5mL) and treated with 2 equivalents of sodium borohydride at roomtemperature. After 3 hours, water was added, and the separatedprecipitate was collected by suction filteration, washed with water, anddried to yield compound 50 (93 mg) as a powder. ¹H-NMR (500 MHz, DMSO):11.33 (s, 1H), 8.15 (m, 2H), 7.13 (d, J=7, 2H), 6.92 (s, 2H), 6.65 (m,5H), 4.16 (d, J=6, 2H), 2.77 (s, 6H), 2.14 (s, 6H).

Example 51 Synthesis of5-((4-hydroxy-3,5-dimethylbenzyl)amino)-3-((4-(morpholinomethyl)phenyl)amino)-1H-pyrazole-4-carboxamide51

The intermediate5-amino-3-((4-(morpholinomethyl)phenyl)amino)-1H-pyrazole-4-carboxamidewas prepared in a manner substantially similar to that described for A2of Example 1.

5-amino-3-((4-(morpholinomethyl)phenyl)amino)-1H-pyrazole-4-carboxamide(122 mg) was suspended in EtOH (5 mL) and piperidine (5 drops). Thereaction mixture was heated at 80° C. while stirring, and 1.5equivalents of 3,5-dimethyl-4-hydroxybenzaldehyde was added. After 24hours, the reaction mixture was cooled to room temperature. Theseparated solids were collected by suction filtration and rinsed withethanol to give the crude imine product, which was combined with DMF (1mL) and MeOH (3 mL) and treated with 2 equivalents of sodium borohydrideat room temperature. After 24 hours, water was added, and the separatedprecipitate was collected by suction filteration, washed with water, anddried to yield compound 51 (110 mg) as a powder. ¹H-NMR (500 MHz, DMSO):11.48 (s, 1H) 8.54 (s, 1H), 8.15 (s, 1H), 7.16 (d, J=8, 2H), 7.08 (d,J=8, 2H), 6.92 (s, 2H), 6.66 (s, 3H), 4.17 (d, J=6, 2H), 3.55 (m, 4H),2.31 (s, 4H), 2.14 (s, 6H).

Example 52 Synthesis of5-((4-hydroxy-3,5-dimethylbenzyl)amino)-3-((3-methoxyphenyl)amino)-1H-pyrazole-4-carboxamide52

The intermediate5-amino-3-((3-methoxyphenyl)amino)-1H-pyrazole-4-carboxamide wasprepared in a manner substantially similar to that described for A2 ofExample 1.

5-amino-3-((3-methoxyphenyl)amino)-1H-pyrazole-4-carboxamide (122 mg)was suspended in EtOH (3 mL) and acetic acid (5 drops). The reactionmixture was heated at 80° C. while stirring, and 1.5 equivalents of3,5-dimethyl-4-hydroxybenzaldehyde was added. After 24 hours, thereaction mixture was cooled to room temperature. The separated solidswere collected by suction filtration and rinsed with ethanol to give thecrude imine product, which was then combined with DMF (0.5 mL) and MeOH(2.5 mL) and treated with 2 equivalents of sodium borohydride at roomtemperature. After 4 hours, water was added, and the separatedprecipitate was collected by suction filteration, washed with water, anddried to yield compound 52 (35 mg) as a powder. ¹H-NMR (500 MHz, DMSO):11.52 (s, 1H), 8.63 (s, 1H), 8.15 (s, 1H), 7.05 (t, J=9 Hz, 1H), 6.95(s, 1H), 6.92 (s, 2H), 6.69 (m, 4H), 6.33 (d, J=8 Hz, 1H), 4.17 (d, J=6Hz, 2H), 3.69 (s, 3H), 2.14 (s, 6H).

Example 53 Synthesis of3-((4-(4-fluorobenzamido)phenyl)amino)-5-((4-hydroxy-3,5-dimethylbenzyl)amino)-1H-pyrazole-4-carboxamide53

The intermediate5-amino-3-((4-(4-fluorobenzamido)phenyl)amino)-1H-pyrazole-4-carboxamidewas prepared in a manner substantially similar to that described for A2of Example 1.

5-amino-3-((4-(4-fluorobenzamido)phenyl)amino)-1H-pyrazole-4-carboxamide(84 mg) was suspended in EtOH (5 mL) and piperidine (5 drops). Thereaction mixture was heated at 80° C. while stirring, and 1.5equivalents of 3,5-dimethyl-4-hydroxybenzaldehyde was added. After 18hours, the reaction mixture was cooled to room temperature. Theseparated solids were collected by suction filtration and rinsed withethanol to give the crude imine product, which was then combined withDMF (1 mL) and MeOH (2 mL) and treated with 2 equivalents of sodiumborohydride at room temperature. After 15 minutes, water was added, andthe separated precipitate was collected by suction filteration, washedwith water, and dried to yield compound 53 (97 mg) as a powder. ¹H-NMR(500 MHz, DMSO): 11.47 (s, 1H), 10.04 (s, 1H), 8.59 (s, 1H), 8.16 (s,1H), 8.01 (m, 2H), 7.54 (d, J=9, 2H), 7.34 (t, J=18 Hz, 2H), 7.23 (d,J=9 Hz, 2H), 6.93 (s, 2H), 6.68 (s, 3H), 8.18 (d, J=6 Hz, 2H), 2.15 (s,6H).

Example 54 Synthesis of3-((4-(1H-pyrazol-3-yl)phenyl)amino)-5-((4-hydroxy-3,5-dimethylbenzyl)amino)-1H-pyrazole-4-carboxamide54

The intermediate3-((4-(1H-pyrazol-3-yl)phenyl)amino)-5-amino-1H-pyrazole-4-carboxamidewas prepared in a manner substantially similar to that described for A2of Example 1.

3-((4-(1H-pyrazol-3-yl)phenyl)amino)-5-amino-1H-pyrazole-4-carboxamide(515 mg) was suspended in EtOH (5 mL) and piperidine (5 drops). Thereaction mixture was heated at 80° C. while stirring, and 1.5equivalents of 3,5-dimethyl-4-hydroxybenzaldehyde was added. After 24hours, the reaction mixture was cooled to room temperature. Theseparated solids were collected by suction filtration and rinsed withethanol to give the crude imine product which then combined with DMF(0.5 mL) and MeOH (1.5 mL) and treated with 2 equivalents of sodiumborohydride at room temperature. After 24 hour, water was added, and theseparated precipitate was collected by suction filteration, washed withwater, and dried to yield compound 54 (19 mg) as a powder. ¹H-NMR (500MHz, DMSO): 13.02 (broad s, 0.4H), 12.65 (broad s, 0.6H), 11.52 (s, 1H),8.90-8.60 (2 broad s, 1H), 8.16 (s, 1H), 7.80-7.18 (m, 5H), 6.93 (s,2H), 6.69 (s, 3H), 6.53 (m, 1H), 4.18 (d, 2H), 2.15 (s, 6H).

Example 55 Synthesis of5-((4-hydroxy-3,5-dimethylbenzyl)amino)-3-((4-(2-methoxybenzamido)phenyl)amino)-1H-pyrazole-4-carboxamide55

5-amino-3-((4-(2-methoxybenzamido)phenyl)amino)-1H-pyrazole-4-carboxamidewas prepared in a manner substantially similar to that described for A2of Example 1.

5-amino-3-((4-(2-methoxybenzamido)phenyl)amino)-1H-pyrazole-4-carboxamide(49 mg) was suspended in EtOH (5 mL) and piperidine (5 drops). Thereaction mixture was heated at 80° C. while stirring, and 1.5equivalents of 3,5-dimethyl-4-hydroxybenzaldehyde was added. After 22hours, the reaction mixture was cooled to room temperature. Theseparated solids were collected by suction filtration and rinsed withethanol to give the crude imine product which then combined with DMF(0.5 mL) and MeOH (2.5 mL) and treated with 2 equivalents of sodiumborohydride at room temperature. After 3 hours, water was added, and theseparated precipitate was collected by suction filteration, washed withwater, and dried to yield compound 54 (34 mg) as a powder. ¹H-NMR (500MHz, DMSO): 11.46 (s, 1H), 9.88 (s, 1H), 8.59 (s, 1H), 8.16 (s, 1H),7.65 (d, J=7 Hz, 1H), 7.54 (d, J=9 Hz, 2H), 7.48 (t, J=8 Hz, 1H), 7.23(d, J=9 Hz, 2H), 7.16 (d, J=8 Hz, 1H), 7.05 (t, J=8 Hz, 1H), 6.93 (s,2H), 6.68 (s, 3H), 4.18 (d, J=6 Hz, 2H), 3.90 (s, 3H), 2.15 (s, 6H).

Example 56 Synthesis of5-((4-hydroxy-3,5-dimethylbenzyl)amino)-3-((4-(3-methoxybenzamido)phenyl)amino)-1H-pyrazole-4-carboxamide56

The intermediate5-amino-3-((4-(3-methoxybenzamido)phenyl)amino)-1H-pyrazole-4-carboxamidewas prepared in a manner substantially similar to that described for A2of Example 1.

5-amino-3-((4-(3-methoxybenzamido)phenyl)amino)-1H-pyrazole-4-carboxamide(85 mg) was suspended in EtOH (5 mL) and piperidine (5 drops). Thereaction mixture was heated at 80° C. while stirring, and 1.5equivalents of 3,5-dimethyl-4-hydroxybenzaldehyde was added. After 22hours, the reaction mixture was cooled to room temperature. Theseparated solids were collected by suction filtration and rinsed withethanol to give the crude imine product which was then combined with DMF(0.5 mL) and MeOH (2.5 mL) and treated with 2 equivalents of sodiumborohydride at room temperature. After 6 hours, water was added, and theseparated precipitate was collected by suction filteration, washed withwater, and dried to yield compound 56 (75 mg) as a powder. ¹H-NMR (500MHz, DMSO): 11.82 (s, 1H), 10.00 (s, 1H), 8.59 (s, 1H), 8.16 (s, 1H),7.54 (m, 3H), 7.47 (m, 1H), 7.42 (t, J=8 Hz, 1H), 7.23 (d, J=8 Hz, 2H),7.13 (dd, 1H), 6.93 (s, 2H), 6.68 (s, 3H), 4.18 (d, J=6 Hz, 2H), 3.83(s, 3H), 2.15 (s, 6H).

Example 57 Synthesis of5-((4-hydroxy-3,5-dimethylbenzyl)amino)-3-((4-(4-methoxybenzamido)phenyl)amino)-1H-pyrazole-4-carboxamide57

The intermediate5-amino-3-((4-(4-methoxybenzamido)phenyl)amino)-1H-pyrazole-4-carboxamidewas prepared in a manner substantially similar to that described for A2of Example 1.

5-amino-3-((4-(4-methoxybenzamido)phenyl)amino)-1H-pyrazole-4-carboxamide(73 mg) was suspended in EtOH (5 mL) and piperidine (5 drops). Thereaction mixture was heated at 80° C. while stirring, and 1.5equivalents of 3,5-dimethyl-4-hydroxybenzaldehyde was added. After 22hours, the reaction mixture was cooled to room temperature. Theseparated solids were collected by suction filtration and rinsed withethanol to give the crude imine product which was then combined with DMF(0.5 mL) and MeOH (2.5 mL) and treated with 2 equivalents of sodiumborohydride at room temperature. After 1 hour, water was added, and theseparated precipitate was collected by suction filteration, washed withwater, and dried to yield compound 57 (69 mg) as a powder. ¹H-NMR (500MHz, DMSO): 11.80 (s, 1H), 9.87 (s, 1H), 8.56 (s, 1H), 8.16 (s, 1H),7.94 (m, 2H), 7.54 (d, J=9 Hz, 2H), 7.22 (d, J=8 Hz, 2H), 7.05 (m, 2H),6.93 (s, 2H), 6.68 (s, 3H), 4.18 (d, J=6 Hz, 2H), 3.84 (m, 3H), 2.15 (s,1H).

Example 58 Synthesis of5-((4-hydroxy-3,5-dimethylbenzyl)amino)-3-((4-(4-isopropylpiperidin-1-yl)phenyl)amino)-1H-pyrazole-4-carboxamide58

The intermediate5-amino-3-((4-(4-isopropylpiperidin-1-yl)phenyl)amino)-1H-pyrazole-4-carboxamidewas prepared in a manner substantially similar to that described for A2of Example 1.

5-amino-3-((4-(4-isopropylpiperidin-1-yl)phenyl)amino)-1H-pyrazole-4-carboxamide(151 mg) was suspended in EtOH (5 mL) and piperidine (5 drops). Thereaction mixture was heated at 80° C. while stirring, and 1.5equivalents of 3,5-dimethyl-4-hydroxybenzaldehyde was added. After 22hours, the reaction mixture was cooled to room temperature. Theseparated solids were collected by suction filtration and rinsed withethanol to give the crude imine product which was then combined with DMF(1 mL) and MeOH (3 mL) and treated with 2 equivalents of sodiumborohydride at room temperature. After 24 hours, water was added, andthe separated precipitate was collected by suction filteration, washedwith water, and dried to yield compound 58 (142 mg) as a powder. ¹H-NMR(500 MHz, DMSO): 11.36 (s, 1H), 8.22 (s, 1H), 8.13 (s, 1H), 7.12 (d, J=9Hz, 2H), 6.92 (s, 2H), 8.79 (d, J=9 Hz, 2H), 6.63 (m, 3H), 4.16 (d, J=6Hz, 2H), 5.50 (d, J=12 Hz, 2H), 2.46 (m, 2H), 2.14 (s, 6H), 1.71 (d,2H), 1.44 (m, 1H), 1.28 (m, 2H), 1.08 (m, 1H), 0.88 (d, J=7 Hz, 6H).

Example 59 Synthesis of5-((4-hydroxy-3,5-dimethylbenzyl)amino)-3-((4-(3-oxomorpholino)phenyl)amino)-1H-pyrazole-4-carboxamide59

The intermediate5-amino-3-((4-(3-oxomorpholino)phenyl)amino)-1H-pyrazole-4-carboxamidewas prepared in a manner substantially similar to that described for A2of Example 1.

5-amino-3-((4-(3-oxomorpholino)phenyl)amino)-1H-pyrazole-4-carboxamide(400 mg) was suspended in EtOH (8 mL) and piperidine (5 drops). Thereaction mixture was heated at 80° C. while stirring, and 1.4equivalents of 3,5-dimethyl-4-hydroxybenzaldehyde was added. After 20hours, the reaction mixture was cooled to room temperature. Theseparated solids were collected by suction filtration and rinsed withethanol to give the crude imine product. Some of the crude imine (50 mg)was combined with DMF (1 mL) and MeOH (1 mL) and treated with 2equivalents of sodium borohydride at room temperature. After 18 hours,water was added, and the separated precipitate was collected by suctionfilteration, washed with water, and dried to yield compound 59 (36 mg)as a powder. ¹H-NMR (500 MHz, DMSO): 2.15 (s, 6H), 3.64 (t, 2H), 3.94(t, 2H), 4.15 (s, 2H), 4.18 (d, 2H), 6.68 (m, 3H), 6.93 (s, 2H), 7.15(t, 2H), 7.22 (d, 2H), 8.15 (s, 1H), 8.63 (s, 1H), 11.53 (s, 1H).

Example 61 Synthesis of3-((4-(cyanomethyl)phenyl)amino)-5-((4-hydroxy-3,5-dimethylbenzyl)amino)-1H-pyrazole-4-carboxamide61

The intermediate5-amino-3-((4-(cyanomethyl)phenyl)amino)-1H-pyrazole-4-carboxamide wasprepared in a manner substantially similar to that described for A2 ofExample 1.

5-amino-3-((4-(cyanomethyl)phenyl)amino)-1H-pyrazole-4-carboxamide (86mg) was suspended in EtOH (5 mL) and acetic acid (5 drops). The reactionmixture was heated at 80° C. while stirring, and 1.5 equivalents of3,5-dimethyl-4-hydroxybenzaldehyde was added. After 24 hours, thereaction mixture was cooled to room temperature. The separated solidswere collected by suction filtration and rinsed with ethanol to give thecrude imine product. A portion of the crude imine product was thencombined with DMF (0.5 mL) and MeOH (1.5 mL) and treated with 2equivalents of sodium borohydride at room temperature. After 2 hours,water was added, and the separated precipitate was collected by suctionfilteration, washed with water, and dried to yield compound 61 (62 mg)as a powder. ¹H-NMR (500 MHz, DMSO): 11.51 (s, 1H), 8.65 (s, 1H), 8.14(s, 1H), 7.24 (d, J=9 Hz, 2H), 7.14 (d, J=9 Hz, 2H), 6.92 (s, 2H), 6.67(m, 3H), 4.18 (d, J=6 Hz, 2H), 3.87 (s, 2H), 2.15 (s, 6H).

Example 62 Synthesis of5-((4-hydroxy-3,5-dimethylbenzyl)amino)-3-((4-(4-(trifluoromethyl)benzamido)phenyl)amino)-1H-pyrazole-4-carboxamide62

The intermediate5-amino-3-((4-(4-(trifluoromethyl)benzamido)phenyl)amino)-1H-pyrazole-4-carboxamidewas prepared in a manner substantially similar to that described for A2of Example 1.

5-amino-3-((4-(4-(trifluoromethyl)benzamido)phenyl)amino)-1H-pyrazole-4-carboxamide(101 mg) was suspended in EtOH (5 mL) and acetic acid (5 drops). Thereaction mixture was heated at 80° C. while stirring, and 1.5equivalents of 3,5-dimethyl-4-hydroxybenzaldehyde was added. After 24hours, the reaction mixture was cooled to room temperature. Theseparated solids were collected by suction filtration and rinsed withethanol to give the crude imine product which was then combined with DMF(1 mL) and MeOH (3 mL) and treated with 2 equivalents of sodiumborohydride at room temperature. After 2 hours, water was added, and theseparated precipitate was collected by suction filteration, washed withwater, and dried to yield compound 62 (15 mg) as a powder. ¹H-NMR (500MHz, DMSO): 11.48 (s, 1H), 10.26 (s, 1H), 8.63 (s, 1H), 8.16 (s, 1H),8.13 (d, J=8 Hz, 2H), 7.90 (d, J=9 Hz, 2H), 7.58 (d, 2H), 7.25 (d, J=7Hz, 2H), 6.93 (s, 2H), 6.69 (s, 3H), 4.18 (d, J=7 Hz, 2H), 2.15 (s, 6H).

Example 63 Synthesis of5-((4-hydroxy-3,5-dimethylbenzyl)amino)-3-((4-(4-methylpiperidin-1-yl)phenyl)amino)-1H-pyrazole-4-carboxamide63

The intermediate5-amino-3-((4-(4-methylpiperidin-1-yl)phenyl)amino)-1H-pyrazole-4-carboxamidewas prepared in a manner substantially similar to that described for A2of Example 1.

5-amino-3-((4-(4-methylpiperidin-1-yl)phenyl)amino)-1H-pyrazole-4-carboxamide(114 mg) was suspended in EtOH (5 mL) and piperidine (5 drops). Thereaction mixture was heated at 80° C. while stirring, and 1.5equivalents of 3,5-dimethyl-4-hydroxybenzaldehyde was added. After 21hours, the reaction mixture was cooled to room temperature. Theseparated solids were collected by suction filtration and rinsed withethanol to give the crude imine product, which was then combined withDMF (0.5 mL) and MeOH (2 mL) and treated with 2 equivalents of sodiumborohydride at room temperature. After 30 minutes, water was added, andthe separated precipitate was collected by suction filteration, washedwith water, and dried to yield compound 63 (30 mg) as a powder. ¹H-NMR(500 MHz, DMSO): 11.36 (s, 1H), 8.21 (s, 2H), 8.12 (s, 2H), 7.10 (s,2H), 6.92 (s, 2H), 6.79 (d, 2H), 6.62 (s, 2H), 4.16 (d, 2H), 3.43 (d,2H), 2.54 (s, 1H), 2.14 (s, 6H), 1.67 (d, 2H), 1.43 (m, 1H), 1.26 (m,2H), 0.93 (d, 3H).

Example I Mass Spectrometry Data for Kinase Inhibitors

Mass spectrometry data for the kinase inhibitors are summarized in Table1 below.

TABLE 1 MS positive Compound ion mode (m/z) 1 478 2 471 3 437 4 465 5472 6 417 7 438 8 451 9 429 10 450 11 439 12 452 13 493 14 465 15 499 16429 17 512 18 428 19 418 20 382 21 408 22 392 23 532 24 533 25 453 26466 27 435 28 499 29 464 30 449 31 526 32 485 33 436 34 469 35 364 36478 37 427 38 391 39 521 40 381 41 456 42 341 43 349 44 514 45 449 46453 47 367 48 461 49 505 50 395 51 450 52 382 53 489 54 418 55 501 56499 57 499 58 477 59 451 61 391 62 539 63 449

Example II Enzymatic Assays for Kinase Inhibitory Activity

For most assays, kinase-tagged T7 phage strains were prepared in an E.coli host derived from the BL21 strain. E. coli were grown to log-phaseand infected with T7 phage and incubated with shaking at 32° C. untillysis. The lysates were centrifuged and filtered to remove cell debris.The remaining kinases were produced in HEK-293 cells and subsequentlytagged with DNA for quantitative PCR (qPCR) detection.

Streptavidin-coated magnetic beads were treated with biotinylated smallmolecule ligands for 30 minutes at room temperature to generate affinityresins for kinase assays. The liganded beads were blocked with excessbiotin and washed with blocking buffer (SeaBlock (Pierce), 1% BSA, 0.05%Tween 20, 1 mM DTT) to remove unbound ligand and to reduce nonspecificbinding. Binding reactions were assembled by combining kinases, ligandedaffinity beads, and test compounds in 1× binding buffer (20% SeaBlock,0.17×PBS, 0.05% Tween 20, 6 mM DTT). All reactions were performed inpolystyrene 96-well plates in a final volume of 0.135 mL. The assayplates were incubated at room temperature with shaking for 1 hour andthe affinity beads were washed with wash buffer (1×PBS, 0.05% Tween 20).The beads were then re-suspended in elution buffer (1×PBS, 0.05% Tween20, 0.5 μM non-biotinylated affinity ligand) and incubated at roomtemperature with shaking for 30 minutes. The kinase concentration in theeluates was measured by qPCR.

An 11-point 3-fold serial dilution of each test compound was prepared in100% DMSO at 100× final test concentration and subsequently diluted to1× in the assay (final DMSO concentration=1%). Most K_(d) values weredetermined using a compound top concentration=30,000 nM. If the initialK_(d) determined was <0.5 nM, (the lowest concentration tested), themeasurement was repeated with a serial dilution starting at a lower topconcentration. A more detailed description of this assay may be found inFabian, M. A. et al. Nat. Biotechnol. 2005, 23, 329-336, which isincorporated herein in its entirety.

The biological results of inhibition of the kinase domain protein of RCkinase (RCK) and JAK2 and JAK3 are summarized in Tables 2 and 3, whereinA represents a K_(d) of <50 nM; B represents 50 nM<K_(d)<100 nM; Crepresents 100 nM<K_(d)<1000 nM; and D represents a K_(d)>1000 nM.

Additionally, RCK:JAK2 selectivity, as measured by the ratio K_(d)(JAK2): K_(d) (RCK) is represented as follows: A represents K_(d)(JAK2): K_(d) (RCK)>100; B represents 10<K_(d) (JAK2): K_(d) (RCK)<100;C represents 1<K_(d) (JAK2): K_(d) (RCK)<10; and D represents K_(d)(JAK2): K_(d) (RCK)<1.

Similarly, RCK:JAK3 selectivity, as measured by the ratio K_(d) (JAK3):K_(d) (RCK) is represented as follows: A represents K_(d) (JAK3): K_(d)(RCK)>100; B represents 10<K_(d) (JAK3): K_(d) (RCK)<100; C represents1<K_(d) (JAK3): K_(d) (RCK)<10; and D represents K_(d) (JAK3): K_(d)(RCK)<1.

TABLE 2 RCK: RCK: RCK JAK2 JAK3 JAK2 JAK3 Activity Activity Activityselectivity selectivity Compound Level Level Level ratio ratio

A C C A A

A C D B A

A C D B A

C D D B B

C D D B B

A D D A A

B C D C B

B D D B B

B D D B A

B D D B A

B C D C B

C D D B B

D D D B B

D D D C B

B D D B B

B D D B B

A C C A A

D D D C C

C D D A A

C D D C B

D D D C —

C D D C B

A D D B B

A D D B A

C D D C B

C D D B B

C D D B B

B D D B B

A C D B B

B D D B B

A D D B B

A C C C B

B C D C B

B D D B B

B C D C B

A C D B A

A D D B A

C D D A A

B A A B B

D D D C C

A C D B A

D D D B B

D D D D C

C D D B B

A C C C B

A C D B B

D D D C C

C C D C B

A C C A A

C D D C C

A C D B B

D D D C C

C D D A A

C D D B B

C D D B B

C D D B A

B D D A A

C D D B B

C D D B B

D D D C C

C D D B B

C D D B B

D D D C C

TABLE 3 RCK: RCK: RCK JAK2 JAK3 JAK2 JAK3 Activity Activity Activityselectivity selectivity Compound Level Level Level ratio ratio

A A B C B

A A A D C

A A A D C

A A A D C

A A B C C

A A A D C

A A A D C

A N/A N/A N/A N/A

A A A D C

A A A C C

A A A D D

A A A D C

A A A D C

A A A D C

A A A D C

A A A C C

A A A C C

B A B D C

A A A D C

A A A D C

A A B D C

B A A D D

A A A C D

A A A D C

A A A D D

A A A C C

A A A C C

A A A D C

A A A C C

A A B C C

A A A D C

A A A D D

A A A D D

A A A D C

A A A D D

A A A D D

A A A — —

A A A C C

A A A D C

A A A D D

A A A D C

A A A D D

B A A D D

A A A C C

A A A D D

A A A D C

C B C D D

A A A D D

A A A D C

C A C D C

A A A D D

A A A D D

A A A C C

A A A D C

A A A B B

A A A C B

A A A B B

B C C C C

A A A D C

A A A D C

B C C C C

A A B D C

The examples set forth above are provided to give those of ordinaryskill in the art with a complete disclosure and description of how tomake and use the claimed embodiments, and are not intended to limit thescope of what is disclosed herein. Modifications that are obvious topersons of skill in the art are intended to be within the scope of thefollowing claims. All publications, patents, and patent applicationscited in this specification are incorporated herein by reference as ifeach such publication, patent or patent application were specificallyand individually indicated to be incorporated herein by reference.

What is claimed is:
 1. A compound of Formula I:

or a stereoisomer, enantiomer, mixture of enantiomers, or mixture ofdiastereomers thereof; or a pharmaceutically acceptable salt thereof;wherein: R¹ is C₆₋₁₄aryl, heteroaryl, or heterocyclyl; R² and R³ areeach independently C₁₋₆ alkyl or C₃₋₁₀ cycloalkyl; wherein each alkyl,cycloalkyl, aryl, heteroaryl or heterocyclyl is optionally substitutedwith one or more substituents Q, where each Q is independently selectedfrom halo, C₁₋₆ alkyl, heteroaryl, and heterocyclyl, each of which isfurther optionally substituted with one or more C₁₋₆ alkyl; with theproviso that the compound is not 3-((3-chlorophenyl)amino)-5-((4-hydroxy-3,5-dimethylbenzyl)amino)-1H-pyrazole-4-carboxamide.
 2. The compound ofclaim 1, wherein R¹ is C₆₋₁₄ aryl or heteroaryl, each of which isoptionally substituted with one or more substituents Q.
 3. The compoundof claim 1, wherein R¹is C₆₋₁₄ aryl, optionally substituted with one ormore substituents Q.
 4. The compound of claim 1, wherein R¹is phenyl,optionally substituted with one or more substituents Q.
 5. The compoundof claim 4, wherein Q is independently selected from fluoro, chloro,bromo, iodo, methyl, morpholinyl, dimethylmorpholinyl, pyrrolyl,isopropylpiperazinyl, methylpiperazinyl, pyridinyl, andbenzylpiperazinyl.
 6. The compound of claim 3, wherein R¹is3-methyl-4-morpholinophenyl, 3-chloro-4-morpholinophenyl,4-morpholinophenyl, 4-(2,6-dimethylmorpholino)phenyl,4-(1H-pyrrol-1-yl)phenyl, 4-(4-isopropylpiperazin-l-yl)phenyl,4-(pyridin-2-yl)phenyl, 4-(4-methylpiperazin-l-yl)phenyl,3-chloro-4-(2,6-dimethylmorpholino)phenyl, 4-(pyridin-3-yl)phenyl, or3-chloro-4-(4-isopropylpiperazin-l -yl)phenyl.
 7. The compound of claim1, wherein R¹ is heteroaryl, optionally substituted with one or moresubstituents Q.
 8. The compound of claim 7, wherein R¹ is 5- or6-membered heteroaryl, each of which is optionally substituted with oneor more substituents Q.
 9. The compound of claim 8, wherein R¹ ispyridinyl, optionally substituted with one or more substituents Q. 10.The compound of claim 9, wherein R¹ is2-morpholino-3-chloropyridin-5-yl, 2-morpholinopyridin-5-yl,5-morpholinopyridin-2-yl, 2-morpholino-3-methylpyridin-5-yl,2-(4-isopropylpiperazin-1-yl)-3-methylpyridin-5-yl, or2-(4-methylpiperazin-1-yl)-3-methylpyridin-5-yl.
 11. The compound ofclaim 1, wherein R² is C₁₋₆ alkyl.
 12. The compound of claim 1, whereinR² is methyl.
 13. The compound of claim 1, wherein R³ is C₁₋₆ alkyl. 14.The compound of claim 1, wherein R³ is methyl.
 15. The compound of claim1 selected from the group consisting of:

and stereoisomers, enantiomers, mixtures of enantiomers, and mixtures ofdiastereomers thereof; and pharmaceutically acceptable salts thereof.16. A pharmaceutical composition comprising the compound of claim 1, andone or more pharmaceutically acceptable excipients.
 17. Thepharmaceutical composition of claim 16, wherein the composition isformulated for single dose administration.
 18. The pharmaceuticalcomposition of claim 16, wherein the composition is formulated as oral,parenteral, or intravenous dosage form.
 19. The pharmaceuticalcomposition of claim 18, wherein the oral dosage form is a tablet orcapsule.
 20. The pharmaceutical composition of claim 16, furthercomprising a second therapeutic agent.
 21. A compound of Formula I:

or a stereoisomer, enantiomer, mixture of enantiomers, or mixture ofdiastereomers thereof; or a pharmaceutically acceptable salt thereof;wherein: R¹ is C₆₋₁₄ aryl, heteroaryl, or heterocyclyl; R² and R³ areeach independently C₁₋₆ alkyl or C₃₋₁₀ cycloalkyl; wherein each alkyl,cycloalkyl, aryl, heteroaryl or heterocyclyl is optionally substitutedwith one or more substituents Q, where each Q is independently selectedfrom halo, C₁₋₆ alkyl, C₁₋₆ alkoxy, aryl, heteroaryl, and heterocyclyl,each of which is further optionally substituted with one or more C₁₋₆alkyl, halo, aralkyl, dialkylamino, heterocyclyl, heterocyclylalkyl, andheterocyclylcarbonyl; with the proviso that the compound is not3-((3-chlorophenyl)amino)-5-((4-hydroxy-3,5-dimethylbenzyl)amino)-1H-pyrazole-4-carboxamide.22. The compound of claim 21, wherein R¹ is C₆₋₁₄ aryl or heteroaryl,each of which is optionally substituted with one or more substituents Q.23. The compound of claim 21, wherein R¹ is C₆₋₁₄ aryl, optionallysubstituted with one or more substituents Q.
 24. The compound of claim21, wherein R¹ is phenyl, optionally substituted with one or moresubstituents Q.
 25. The compound of claim 24, wherein Q is independentlyselected from fluoro, chloro, bromo, iodo, methyl, morpholinyl,dimethylmorpholinyl, pyrrolyl, isopropylpiperazinyl, methylpiperazinyl,pyridinyl, benzylpiperazinyl, phenyl, imidazolyl, methoxy, tert-butyl,indazolyl, methylpipiperidinyl, (pyrrolidinecarbonyl)piperazinyl,flouropiperidinyl, dimethylpyranyl, piperidinyl, benzyl,1,1-dioxidothiomorpholino, pyrrolidinylmethyl, dimethylamino, oxazolyl,(piperidinecarbonyl)piperazinyl, acetamido, (pyrimidinyl)piperizinyl,piperidinylmethyl, thiomorpholinyl fluorophenylamido,methoxyphenylamido, isopropylpiperidinyl, cyanomethyl,(trifluoromethyl)phenylamido, and oxomorpholinyl.
 26. The compound ofclaim 23, wherein R¹ is 3-methyl-4-morpholinophenyl,3-chloro-4-morpholinophenyl, 4-morpholinophenyl,4-(2,6-dimethylmorpholino)phenyl, 4-(1H-pyrrol-1-yl)phenyl, 4-(4-isopropylpiperazin-1-yl)phenyl, 4-(pyridin- 2-yl)phenyl,4-(4-methylpiperazin-1-yl)phenyl,3-chloro-4-(2,6-dimethylmorpholino)phenyl, 4-(pyridin-3-yl)phenyl,3-chloro-4-(4-isopropylpiperazin-1-yl)phenyl, 1,1′-biphenyl,4-(1H-imidazol-1-yl)phenyl, 4-methoxyphenyl, 4-tert-butylphenyl,4-(4-methyl-[1,4′-bipiperidin]-1′-yl)phenyl,4-(4-(morpholine-4-carbonyl)piperazin-l-yl)phenyl,4-(4-fluoropiperidin-1-yl)phenyl, 4-(piperidin-1-yl)phenyl.3-chloro-4-(2,6-dimethylmorpholino)phenyl,3-methyl-4-(4-methylpiperazin-1-yl)phenyl, 3-methyl-4-(piperidin-1-yl)phenyl, 4-(4-benzylpiperazin-1-yl)-3-methylphenyl,4-(1,1-dioxidothiomorpholino)phenyl,(5-(piperidin-1-yl)pyridine-2-yl)phenyl,4-(4-chloropiperidin-1-yl)phenyl, 4-(pyrrolidin-l -ylmethyl)phenyl,4-(4-(dimethylamino)piperidin-1-yl)phenyl, 3-fluoro-4-morpholinophenyl,4-(oxazol-5-yl)phenyl,4-(4-(piperidine-1-carbonyl)piperazin-1-yl)phenyl, 3-acetamidophenyl,3-chloro-4-(4-methylpiperazin-l-yl)phenyl, 4-fluorophenyl,3-cyanophenyl, 4-(4-(pyrimidin-2-yl)piperazin-l-yl)phenyl,4-(piperidin-l-ylmethyl)phenyl, 4-thiomorpholinophenyl, 4-aminophenyl,4-(aminosulfonyl)phenyl, 4-(dimethylamino)phenyl,4-(morpholinomethyl)phenyl, 2-methoxyphenyl,4-(4-fluorophenylamido)phenyl, 4-(4,5-dihydro-1H-pyrazol-3-yl)phenyl,4-(2-methoxyphenylamido)phenyl, 4-(3-methoxyphenylamido)phenyl,4-(4-methoxyphenylamido)phenyl, 4-(4-isopropylpiperidin-1-yl)phenyl4-(3-oxomorpholinyl)phenyl, 4-(2-cyanomethyl)phenyl,4((4-trifluoromethyl)phenylamido)phenyl, or4-(4-methylpiperidin-1-yl)phenyl.
 27. The compound of claim 21, whereinR¹ is heteroaryl, optionally substituted with one or more subsubstituents Q.
 28. The compound of claim 27, wherein R¹ is 5- or6-membered heteroaryl, each of which is optionally substituted with oneor more substituents Q.
 29. The compound of claim 27, wherein R¹ isindazolyl, optionally substituted with one or more substituents Q. 30.The compound of claim 28, wherein R¹ is pyridinyl, optionallysubstituted with one or more substituents Q.
 31. The compound of claim30, wherein R¹ is 2-morpholino-3-chloropyridin-5-yl,2-morpholinopyridin-5-yl, 5-morpholinopyridin-2-yl,2-morpholino-3-methylpyridin-5-yl,2-(4-isopropylpiperazin-1-yl)-3-methylpyridin-5-yl,2-(4-methylpiperazin-1-yl)-3-methylpyridin-5-yl,6-(2,6-dimethyltetrahydro-2H-pyran-4-yl)pyridin-3-yl, or2-(4-(pyrrolidin-1-yl)piperidin-1-yl)pyridin-5-yl.
 32. The compound ofclaim 21, wherein R² is C₁₋₆ alkyl.
 33. The compound of claim 21,wherein R² is methyl.
 34. The compound of claim 21, wherein R³ is C₁₋₆alkyl.
 35. The compound of claim 21, wherein R³ is methyl.
 36. Thecompound of claim 21 selected from the group consisting of:

and stereoisomers, enantiomers, mixtures of enantiomers, and mixtures ofdiastereomers thereof; and pharmaceutically acceptable salts thereof.37. A pharmaceutical composition comprising the compound of claim 21,and one or more pharmaceutically acceptable excipients.
 38. Thepharmaceutical composition of claim 37, wherein the composition isformulated for single dose administration.
 39. The pharmaceuticalcomposition of claim 37, wherein the composition is formulated as oral,parenteral, or intravenous dosage form.
 40. The pharmaceuticalcomposition of claim 39, wherein the oral dosage form is a tablet orcapsule.
 41. The pharmaceutical composition of claim 37, furthercomprising a second therapeutic agent.